rs202014478

chr2-178672473-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):c.34864G>A(p.Val11622Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,599,106 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V11622V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (12 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:18
• Conservation: PhyloP100: 0.00300

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]

LOC124906100 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.004096329).
• BP6: Variant 2-178672473-C-T is Benign according to our data. Variant chr2-178672473-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46909.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=7, Likely_benign=7}. Variant chr2-178672473-C-T is described in Lovd as [Benign]. Variant chr2-178672473-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00279 (424/151744) while in subpopulation NFE AF= 0.00499 (338/67748). AF 95% confidence interval is 0.00455. There are 0 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.34864G>A	p.Val11622Ile	missense_variant	154/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+27972C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.34864G>A	p.Val11622Ile	missense_variant	154/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.503-62031C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 424 AN: 151626 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00224

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00499

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00330 AC: 780 AN: 236296 Hom.: 3 AF XY: 0.00328 AC XY: 420 AN XY: 128108

Gnomad AFR exome AF: 0.000857

Gnomad AMR exome AF: 0.00118

Gnomad ASJ exome AF: 0.000981

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000256

Gnomad FIN exome AF: 0.00210

Gnomad NFE exome AF: 0.00598

Gnomad OTH exome AF: 0.00320

GnomAD4 exome AF: 0.00440 AC: 6367 AN: 1447362 Hom.: 12 Cov.: 31 AF XY: 0.00427 AC XY: 3068 AN XY: 719340

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00149

Gnomad4 ASJ exome AF: 0.000828

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000219

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.00535

Gnomad4 OTH exome AF: 0.00350

GnomAD4 genome AF: 0.00279 AC: 424 AN: 151744 Hom.: 0 Cov.: 32 AF XY: 0.00245 AC XY: 182 AN XY: 74170

Gnomad4 AFR AF: 0.000603

Gnomad4 AMR AF: 0.00224

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00499

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00437 Hom.: 5

Bravo AF: 0.00297

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00137 AC: 5

ESP6500EA AF: 0.00356 AC: 29

ExAC AF: 0.00364 AC: 440

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:18

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 27, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 20, 2020	Variant summary: TTN c.30961G>A (p.Val10321Ile) results in a conservative amino acid change located in the I-band of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 236296 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.30961G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all laboratories classified as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 29, 2014	p.Val10321Ile in exon 149 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.6% (400/67108) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g). -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 14, 2019	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TTN: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2013

​The p.V10321I variant (also known as c.30961G>A) is located in coding exon 148 of the TTN gene. This alteration results from a G to A substitution at nucleotide position 30961. The valine at codon 10321 is replaced by isoleucine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase asrs202014478.Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.29% (34/11806), having been observed in 0.14% (5/3650) of African American alleles, and in 0.36% (29/8156) of European American alleles. Based on protein sequence alignment, this amino acid position is conserved in available vertebrate species. In addition, this alteration is predicted to be benign by PolyPhen in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.V10321I remains unclear. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Dilated cardiomyopathy 1G Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 11, 2019

- -

TTN-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Tibial muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	17
Dann	Benign	0.96
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.41	T;T;.;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0041	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;D;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.28	N;.;.;.
REVEL	Benign	0.096
Sift	Benign	0.27	T;.;.;.
Polyphen		0.0	.;.;B;B
Vest4		0.094
MVP		0.37
MPC		0.069
ClinPred		0.0060	T
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs202014478; hg19: chr2-179537200; COSMIC: COSV105913479; COSMIC: COSV105913479;