rs77419653

Positions:

• chr2-178748537-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133379.5(TTN):​c.13863G>A​(p.Met4621Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,612,976 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (58 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0130

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053555667).
• BP6: Variant 2-178748537-C-T is Benign according to our data. Variant chr2-178748537-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 192176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178748537-C-T is described in Lovd as [Benign]. Variant chr2-178748537-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00413 (628/152034) while in subpopulation EAS AF= 0.0295 (152/5158). AF 95% confidence interval is 0.0256. There are 11 homozygotes in gnomad4. There are 412 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_133379.5	c.13863G>A	p.Met4621Ile	missense_variant	46/46	ENST00000360870.10	NP_596870.2
TTN	NM_001267550.2	c.11311+4587G>A		intron_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10	c.13863G>A	p.Met4621Ile	missense_variant	46/46	5	NM_133379.5	ENSP00000354117
TTN	ENST00000589042.5	c.11311+4587G>A		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.1223+5567C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 628 AN: 151916 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000723

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0294

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0352

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00648 AC: 1614 AN: 249206 Hom.: 28 AF XY: 0.00599 AC XY: 808 AN XY: 134848

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0309

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0363

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00244 AC: 3568 AN: 1460942 Hom.: 58 Cov.: 35 AF XY: 0.00240 AC XY: 1746 AN XY: 726790

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0228

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.0366

Gnomad4 NFE exome AF: 0.000355

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.00413 AC: 628 AN: 152034 Hom.: 11 Cov.: 32 AF XY: 0.00554 AC XY: 412 AN XY: 74324

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000722

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0295

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0352

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00185 Hom.: 8

Bravo AF: 0.00196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00615 AC: 747

Asia WGS AF: 0.00520 AC: 18 AN: 3474

EpiCase AF: 0.000328

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 26, 2015	p.Met4621Ile in exon 46 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 4% (271/6738) of Finnish chromosome s and 3% (263/8686) of East Asian chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs77419653). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.76
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PROVEAN	Benign	0.17	N
REVEL	Benign	0.056
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.34
MutPred		0.30		Gain of catalytic residue at M4621 (P = 0.0081);
MVP		0.22
ClinPred		0.037	T
GERP RS		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs77419653; hg19: chr2-179613264; COSMIC: COSV60085365; COSMIC: COSV60085365;