rs72650019

Variant names:

• chr2-178694626-C-T
• rs72650019
• NM_001267550.2:c.31399G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178694626-C-T
• chr2-178694626-C-G

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.31399G>A​(p.Val10467Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,560,098 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:21
• Conservation: PhyloP100: 1.39
• Publications: 7 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]

LOC124907912 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063877106).
• BP6: Variant 2-178694626-C-T is Benign according to our data. Variant chr2-178694626-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46848.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.002 (305/152140) while in subpopulation NFE AF = 0.00303 (206/67924). AF 95% confidence interval is 0.00269. There are 2 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.31399G>A	p.Val10467Ile	missense	Exon 117 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.30448G>A	p.Val10150Ile	missense	Exon 115 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.27667G>A	p.Val9223Ile	missense	Exon 114 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.31399G>A	p.Val10467Ile	missense	Exon 117 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.31399G>A	p.Val10467Ile	missense	Exon 117 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.31123G>A	p.Val10375Ile	missense	Exon 115 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152022 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00170 AC: 297 AN: 174314 AF XY: 0.00162

Gnomad AFR exome AF: 0.000402

Gnomad AMR exome AF: 0.000977

Gnomad ASJ exome AF: 0.00103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000568

Gnomad NFE exome AF: 0.00335

Gnomad OTH exome AF: 0.00128

GnomAD4 exome AF: 0.00283 AC: 3984 AN: 1407958 Hom.: 9 Cov.: 30 AF XY: 0.00266 AC XY: 1846 AN XY: 695170

African (AFR) AF: 0.000405 AC: 13 AN: 32134

American (AMR) AF: 0.00107 AC: 40 AN: 37470

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 38 AN: 25216

East Asian (EAS) AF: 0.00 AC: 0 AN: 37222

South Asian (SAS) AF: 0.000303 AC: 24 AN: 79248

European-Finnish (FIN) AF: 0.000918 AC: 46 AN: 50118

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5686

European-Non Finnish (NFE) AF: 0.00341 AC: 3689 AN: 1082608

Other (OTH) AF: 0.00225 AC: 131 AN: 58256

GnomAD4 genome AF: 0.00200 AC: 305 AN: 152140 Hom.: 2 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74384

African (AFR) AF: 0.000457 AC: 19 AN: 41546

American (AMR) AF: 0.00183 AC: 28 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 67924

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00295 Hom.: 4

Bravo AF: 0.00210

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000561 AC: 2

ESP6500EA AF: 0.00284 AC: 23

ExAC AF: 0.000990 AC: 115

Asia WGS AF: 0.00116 AC: 4 AN: 3470

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	-	8	not specified (8)
-	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	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (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	0.077
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0064	T
MetaSVM	Uncertain	-0.24	T
PhyloP100		1.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.27
Sift	Benign	0.21	T
Polyphen		0.98	D
Vest4		0.17
MVP		0.51
MPC		0.40
ClinPred		0.024	T
GERP RS		6.1
Mutation Taster		=65/35	polymorphism

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: rs72650019; hg19: chr2-179559353; COSMIC: COSV99045559;