rs1883085

Variant names:

• chr2-178739433-T-G
• rs1883085
• NM_001267550.2:c.13800A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.13800A>C​(p.Leu4600Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 1,613,754 control chromosomes in the GnomAD database, including 3,847 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (382 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3465 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0120
• Publications: 21 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]

LOC124906101 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033627152).
• BP6: Variant 2-178739433-T-G is Benign according to our data. Variant chr2-178739433-T-G is described in ClinVar as Benign. ClinVar VariationId is 47840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.13800A>C	p.Leu4600Phe	missense_variant	Exon 48 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.13800A>C	p.Leu4600Phe	missense_variant	Exon 48 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0501 AC: 7615 AN: 152096 Hom.: 381 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0464

GnomAD2 exomes AF: 0.0798 AC: 19818 AN: 248428 AF XY: 0.0703

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.0485

Gnomad EAS exome AF: 0.208

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0675

GnomAD4 exome AF: 0.0530 AC: 77500 AN: 1461540 Hom.: 3465 Cov.: 31 AF XY: 0.0512 AC XY: 37256 AN XY: 727054

African (AFR) AF: 0.00947 AC: 317 AN: 33478

American (AMR) AF: 0.229 AC: 10235 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 1238 AN: 26130

East Asian (EAS) AF: 0.189 AC: 7503 AN: 39672

South Asian (SAS) AF: 0.0201 AC: 1735 AN: 86258

European-Finnish (FIN) AF: 0.0546 AC: 2914 AN: 53354

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5766

European-Non Finnish (NFE) AF: 0.0453 AC: 50340 AN: 1111804

Other (OTH) AF: 0.0518 AC: 3124 AN: 60366

GnomAD4 genome AF: 0.0500 AC: 7618 AN: 152214 Hom.: 382 Cov.: 32 AF XY: 0.0516 AC XY: 3837 AN XY: 74402

African (AFR) AF: 0.0118 AC: 491 AN: 41558

American (AMR) AF: 0.138 AC: 2102 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3470

East Asian (EAS) AF: 0.188 AC: 972 AN: 5162

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4818

European-Finnish (FIN) AF: 0.0511 AC: 542 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0454 AC: 3086 AN: 68008

Other (OTH) AF: 0.0450 AC: 95 AN: 2112

Alfa AF: 0.0499 Hom.: 1111

Bravo AF: 0.0610

TwinsUK AF: 0.0483 AC: 179

ALSPAC AF: 0.0488 AC: 188

ESP6500AA AF: 0.0138 AC: 54

ESP6500EA AF: 0.0431 AC: 358

ExAC AF: 0.0722 AC: 8732

Asia WGS AF: 0.0770 AC: 266 AN: 3478

EpiCase AF: 0.0407

EpiControl AF: 0.0431

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Oct 19, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 26, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu 4362Phe in exon 45B of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 4.5% (301/6700) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS/; rs1883085). -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tibial muscular dystrophy Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Apr 20, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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	0.090
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.7
DANN	Benign	0.62
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.50	T;T;.;T;T;T
MetaRNN	Benign	0.0034	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.012
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.23	N;.;.;N;N;.
REVEL	Benign	0.045
Sift	Benign	0.18	T;.;.;T;T;.
Vest4		0.0070
MutPred		0.28		.;.;.;.;Loss of sheet (P = 0.0357);.;
MPC		0.091
ClinPred		0.0013	T
GERP RS		-5.3
Mutation Taster		=96/4	polymorphism (auto)

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: rs1883085; hg19: chr2-179604160; COSMIC: COSV59946480; COSMIC: COSV59946480;