rs1883085

chr2-178739433-T-G

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.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. 14/17 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:12
• Conservation: PhyloP100: -0.0120

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=0.0033627152).
• BP6: Variant 2-178739433-T-G is Benign according to our data. Variant chr2-178739433-T-G is described in ClinVar as [Benign]. Clinvar id is 47840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178739433-T-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
TTN	NM_001267550.2	c.13800A>C	p.Leu4600Phe	missense_variant	48/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.13800A>C	p.Leu4600Phe	missense_variant	48/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.1133+1140T>G		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.0798 AC: 19818 AN: 248428 Hom.: 1717 AF XY: 0.0703 AC XY: 9465 AN XY: 134732

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 SAS exome AF: 0.0191

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

Gnomad4 AFR exome AF: 0.00947

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.0474

Gnomad4 EAS exome AF: 0.189

Gnomad4 SAS exome AF: 0.0201

Gnomad4 FIN exome AF: 0.0546

Gnomad4 NFE exome AF: 0.0453

Gnomad4 OTH exome AF: 0.0518

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

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.0511

Gnomad4 NFE AF: 0.0454

Gnomad4 OTH AF: 0.0450

Alfa AF: 0.0488 Hom.: 561

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 26, 2012	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). -
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 19, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

- -

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	0.090
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
MutationTaster	Benign	1.0	P;P;P;P;P;P
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

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