rs370629962

Variant names:

• chr2-178599024-C-T
• rs370629962
• NM_001267550.2:c.56686G>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.56686G>A​(p.Val18896Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,592,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: 3.21
• Publications: 2 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=0.11621207).
• BP6: Variant 2-178599024-C-T is Benign according to our data. Variant chr2-178599024-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191938.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.56686G>A	p.Val18896Met	missense	Exon 291 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.51763G>A	p.Val17255Met	missense	Exon 241 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.48982G>A	p.Val16328Met	missense	Exon 240 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.56686G>A	p.Val18896Met	missense	Exon 291 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.56530G>A	p.Val18844Met	missense	Exon 289 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.56410G>A	p.Val18804Met	missense	Exon 289 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151862 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 24 AN: 233146 AF XY: 0.0000868

Gnomad AFR exome AF: 0.0000669

Gnomad AMR exome AF: 0.0000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000696

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.0000618 AC: 89 AN: 1440702 Hom.: 0 Cov.: 32 AF XY: 0.0000630 AC XY: 45 AN XY: 714042

African (AFR) AF: 0.000184 AC: 6 AN: 32622

American (AMR) AF: 0.0000238 AC: 1 AN: 41990

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25442

East Asian (EAS) AF: 0.000410 AC: 16 AN: 39042

South Asian (SAS) AF: 0.0000722 AC: 6 AN: 83080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.0000372 AC: 41 AN: 1100740

Other (OTH) AF: 0.000303 AC: 18 AN: 59396

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151980 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74262

African (AFR) AF: 0.0000723 AC: 3 AN: 41496

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.0000430 Hom.: 0

Bravo AF: 0.0000945

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.92
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Polyphen		0.91	P
Vest4		0.44
MVP		0.53
MPC		0.30
ClinPred		0.097	T
GERP RS		5.1
Mutation Taster		=89/11	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: rs370629962; hg19: chr2-179463751; COSMIC: COSV59947137; COSMIC: COSV59947137;