rs758948672

Variant names:

• chr2-178537346-T-C
• rs758948672
• NM_001267550.2:c.99861A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001267550.2(TTN):​c.99861A>G​(p.Ile33287Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,392,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2874043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.99861A>G	p.Ile33287Met	missense_variant	Exon 355 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.99861A>G	p.Ile33287Met	missense_variant	Exon 355 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000154 AC: 3 AN: 194742 AF XY: 0.0000190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000321

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1392020 Hom.: 0 Cov.: 32 AF XY: 0.00000437 AC XY: 3 AN XY: 685734

African (AFR) AF: 0.00 AC: 0 AN: 30564

American (AMR) AF: 0.00 AC: 0 AN: 31792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22376

East Asian (EAS) AF: 0.00 AC: 0 AN: 38818

South Asian (SAS) AF: 0.00 AC: 0 AN: 74382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5458

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1080404

Other (OTH) AF: 0.00 AC: 0 AN: 57216

GnomAD4 genome Cov.: 33

Alfa AF: 0.000112 Hom.: 0

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jul 29, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.91
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D;D;.;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Benign	2.0	.;.;.;M;.;.;M
PhyloP100		1.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.2	N;D;.;.;D;D;.
REVEL	Uncertain	0.46
Sift	Benign	0.048	D;T;.;.;T;T;.
Polyphen		0.37	.;.;.;B;.;.;B
Vest4		0.43
MutPred		0.66		.;.;.;Gain of ubiquitination at K31649 (P = 0.0773);.;.;Gain of ubiquitination at K31649 (P = 0.0773);
MVP		0.58
MPC		0.41
ClinPred		0.26	T
GERP RS		4.6
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758948672; hg19: chr2-179402073;