rs2627037

chr2-178741811-G-Achr2-178741811-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):c.11422C>T(p.Pro3808Ser) variant causes a missense change. The variant allele was found at a frequency of 0.117 in 1,612,258 control chromosomes in the GnomAD database, including 19,490 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4958 hom., cov: 32)
  • Exomes 𝑓: 0.11 (14532 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.37

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.003395766).
• BP6: Variant 2-178741811-G-A is Benign according to our data. Variant chr2-178741811-G-A is described in ClinVar as [Benign]. Clinvar id is 47807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178741811-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.11422C>T	p.Pro3808Ser	missense_variant	48/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.11422C>T	p.Pro3808Ser	missense_variant	48/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.1134-1070G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31031 AN: 151746 Hom.: 4913 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0740

Gnomad OTH AF: 0.170

GnomAD3 exomes AF: 0.182 AC: 44798 AN: 246178 Hom.: 6770 AF XY: 0.166 AC XY: 22208 AN XY: 133546

Gnomad AFR exome AF: 0.423

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.233

Gnomad SAS exome AF: 0.213

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.0742

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.108 AC: 157457 AN: 1460394 Hom.: 14532 Cov.: 33 AF XY: 0.108 AC XY: 78307 AN XY: 726436

Gnomad4 AFR exome AF: 0.429

Gnomad4 AMR exome AF: 0.434

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0732

Gnomad4 OTH exome AF: 0.126

GnomAD4 genome AF: 0.205 AC: 31138 AN: 151864 Hom.: 4958 Cov.: 32 AF XY: 0.210 AC XY: 15567 AN XY: 74224

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.314

Gnomad4 ASJ AF: 0.0988

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0740

Gnomad4 OTH AF: 0.167

Alfa AF: 0.101 Hom.: 2539

Bravo AF: 0.233

TwinsUK AF: 0.0725 AC: 269

ALSPAC AF: 0.0752 AC: 290

ESP6500AA AF: 0.421 AC: 1541

ESP6500EA AF: 0.0732 AC: 597

ExAC AF: 0.174 AC: 21049

Asia WGS AF: 0.217 AC: 751 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 27, 2011	- -
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	GeneDx	Oct 26, 2012	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. -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 21, 2018

- -

Tibial muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2015

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	0.063
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	13
Dann	Benign	0.95
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.50	T;T;.;T;T;T
MetaRNN	Benign	0.0034	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.96	P;P;P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.5	N;.;.;N;N;.
REVEL	Benign	0.16
Sift	Benign	0.76	T;.;.;T;T;.
Vest4		0.040
MPC		0.084
ClinPred		0.0058	T
GERP RS		6.1

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: rs2627037; hg19: chr2-179606538; COSMIC: COSV59946576; COSMIC: COSV59946576;