chr2-178564885-A-G

Position:

• chr2-178564885-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001267550.2(TTN):​c.81247T>C​(p.Ser27083Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,612,456 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. S27083S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00099 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4 O:1
• Conservation: PhyloP100: 1.44

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 -8 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0061344206).
• BP6: Variant 2-178564885-A-G is Benign according to our data. Variant chr2-178564885-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96307.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=4, Uncertain_significance=3}. Variant chr2-178564885-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.81247T>C	p.Ser27083Pro	missense_variant	326/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.2044-17687A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.81247T>C	p.Ser27083Pro	missense_variant	326/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.417-32711A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152128 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000255 AC: 63 AN: 246674 Hom.: 0 AF XY: 0.000262 AC XY: 35 AN XY: 133792

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.0000877

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000356 AC: 520 AN: 1460210 Hom.: 0 Cov.: 37 AF XY: 0.000372 AC XY: 270 AN XY: 726318

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000899

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000454

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152246 Hom.: 3 Cov.: 33 AF XY: 0.000846 AC XY: 63 AN XY: 74434

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000500 Hom.: 0

Bravo AF: 0.00128

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000730 AC: 6

ExAC AF: 0.000248 AC: 30

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000819

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 13, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TTN: BP4 -
not provided, no classification provided	clinical testing	GeneDx	Mar 06, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 18, 2015

The p.Ser24515Pro variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.04% (30/66212) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs186273940). Computational prediction tools and conservation analysi s do not provide strong support for or against an impact to the protein. In summ ary, the clinical significance of the p.Ser24515Pro variant is uncertain. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 04, 2017

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2013

This alteration is classified as likely benign based on a combination of the following: 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	Pathogenic	0.87
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Benign	0.89
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;D;.;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0061	T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.4	D;D;.;.;D;D;.
REVEL	Benign	0.24
Sift	Benign	0.041	D;T;.;.;D;T;.
Polyphen		0.66	.;.;.;P;.;.;P
Vest4		0.48
MVP		0.31
MPC		0.31
ClinPred		0.12	T
GERP RS		4.8

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: rs186273940; hg19: chr2-179429612;