2-178764203-C-T

Variant names:

• chr2-178764203-C-T
• rs148169214
• NM_001267550.2:c.10088G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.10088G>A​(p.Arg3363His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,614,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3363C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:12
• Conservation: PhyloP100: 1.98
• Publications: 4 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00806874).
• BP6: Variant 2-178764203-C-T is Benign according to our data. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577. Variant chr2-178764203-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46577.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000742 (113/152258) while in subpopulation AFR AF = 0.0026 (108/41560). AF 95% confidence interval is 0.0022. There are 1 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.10088G>A	p.Arg3363His	missense_variant	Exon 43 of 363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.10088G>A	p.Arg3363His	missense_variant	Exon 43 of 46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.10088G>A	p.Arg3363His	missense_variant	Exon 43 of 363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.10088G>A	p.Arg3363His	missense_variant	Exon 43 of 46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152140 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000187 AC: 47 AN: 251304 AF XY: 0.000162

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.0000921 AC XY: 67 AN XY: 727210

African (AFR) AF: 0.00233 AC: 78 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111942

Other (OTH) AF: 0.000149 AC: 9 AN: 60392

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152258 Hom.: 1 Cov.: 33 AF XY: 0.000766 AC XY: 57 AN XY: 74450

African (AFR) AF: 0.00260 AC: 108 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000328 Hom.: 0

Bravo AF: 0.000790

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 08, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23861362) -

Dec 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 07, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg3363His in exon 43 of TTN: This variant is not expected to have it clinical s ignificance because it has been identified in 0.2% (9/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS/; dbSNP rs148169214) and due to a lack of conservati on across species, including mammals. Several other mammals (alpaca, dolphin, an d cow) carry a histidine (His; this variant) at this position supporting that th is change may be tolerated. Arg3363His in exon 43 of TTN (rs148169214; allele f requency = 0.2%, 9/4406) -

Feb 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN c.10088G>A (p.Arg3363His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251304 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039). To our knowledge, no occurrence of c.10088G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 46577). Based on the evidence outlined above, the variant was classified as likely benign. -

Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dilated cardiomyopathy 1G Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Early-onset myopathy with fatal cardiomyopathy Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1

Jun 15, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Tibial muscular dystrophy Benign:1

Jun 15, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Oct 31, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.97
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0081	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
PhyloP100		2.0
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.6	D;D;.;.;D;D;.;D
REVEL	Benign	0.19
Sift	Benign	0.23	T;T;.;.;T;T;.;T
Sift4G	Benign	0.095	.;.;.;.;.;.;.;T
Polyphen		0.0, 0.035	.;.;.;B;.;.;B;B
Vest4		0.33
MVP		0.18
MPC		0.10
ClinPred		0.028	T
GERP RS		4.8
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148169214; hg19: chr2-179628930;