2-178732873-C-T

Variant names:

• chr2-178732873-C-T
• rs72648937
• NM_001267550.2:c.16303G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.16303G>A​(p.Val5435Met) variant causes a missense change. The variant allele was found at a frequency of 0.00805 in 1,613,306 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 0.0065 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0082 (68 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:23
• Conservation: PhyloP100: 4.89
• Publications: 13 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007567197).
• BP6: Variant 2-178732873-C-T is Benign according to our data. Variant chr2-178732873-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46614.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00649 (988/152294) while in subpopulation NFE AF = 0.00923 (628/68012). AF 95% confidence interval is 0.00864. There are 6 homozygotes in GnomAd4. There are 446 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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.16303G>A	p.Val5435Met	missense	Exon 55 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.15352G>A	p.Val5118Met	missense	Exon 53 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.12571G>A	p.Val4191Met	missense	Exon 52 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.16303G>A	p.Val5435Met	missense	Exon 55 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.16303G>A	p.Val5435Met	missense	Exon 55 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.16027G>A	p.Val5343Met	missense	Exon 53 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00649 AC: 988 AN: 152176 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00925

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00581 AC: 1440 AN: 247810 AF XY: 0.00607

Gnomad AFR exome AF: 0.00633

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00340

Gnomad NFE exome AF: 0.00857

Gnomad OTH exome AF: 0.00449

GnomAD4 exome AF: 0.00822 AC: 12004 AN: 1461012 Hom.: 68 Cov.: 36 AF XY: 0.00816 AC XY: 5928 AN XY: 726706

African (AFR) AF: 0.00711 AC: 238 AN: 33464

American (AMR) AF: 0.00235 AC: 105 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 286 AN: 26108

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39602

South Asian (SAS) AF: 0.00378 AC: 326 AN: 86174

European-Finnish (FIN) AF: 0.00409 AC: 218 AN: 53362

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5760

European-Non Finnish (NFE) AF: 0.00931 AC: 10353 AN: 1111508

Other (OTH) AF: 0.00767 AC: 463 AN: 60350

GnomAD4 genome AF: 0.00649 AC: 988 AN: 152294 Hom.: 6 Cov.: 33 AF XY: 0.00599 AC XY: 446 AN XY: 74450

African (AFR) AF: 0.00541 AC: 225 AN: 41586

American (AMR) AF: 0.00222 AC: 34 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00923 AC: 628 AN: 68012

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00822 Hom.: 26

Bravo AF: 0.00617

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00637 AC: 25

ESP6500EA AF: 0.00906 AC: 75

ExAC AF: 0.00557 AC: 673

EpiCase AF: 0.00829

EpiControl AF: 0.00736

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	4	not provided (4)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Heart failure (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.95
Eigen	Benign	0.055
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.78	T
PhyloP100		4.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Benign	0.22	T
Polyphen		0.086	B
Vest4		0.40
MVP		0.28
MPC		0.093
ClinPred		0.0069	T
GERP RS		5.3
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72648937; hg19: chr2-179597600; COSMIC: COSV59951885; COSMIC: COSV59951885;