2-178718034-G-T

Variant names:

• chr2-178718034-G-T
• rs879030954
• NM_001267550.2:c.24972C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.24972C>A​(p.Asn8324Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N8324N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.476
• Publications: 0 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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1332789).
• BP6: Variant 2-178718034-G-T is Benign according to our data. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938. Variant chr2-178718034-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466938.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.24972C>A	p.Asn8324Lys	missense_variant	Exon 86 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.24972C>A	p.Asn8324Lys	missense_variant	Exon 86 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461502 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727036

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111712

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

May 22, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 16, 2018

GeneDx

Significance: Likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.69	T;T;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.94	T
PhyloP100		0.48
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.0	D;.;.;.
REVEL	Benign	0.099
Sift	Benign	0.55	T;.;.;.
Polyphen		0.023	.;.;B;B
Vest4		0.39
MutPred		0.55		.;.;Loss of stability (P = 0.0019);Loss of stability (P = 0.0019);
MVP		0.13
MPC		0.098
ClinPred		0.13	T
GERP RS		4.4
Mutation Taster		=87/13	polymorphism

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: rs879030954; hg19: chr2-179582761;