rs72648256

Variant names:

• chr2-178546480-A-T
• rs72648256
• NM_001267550.2:c.94851T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178546480-A-T
• chr2-178546480-A-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.94851T>A​(p.Asp31617Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00291 in 1,612,506 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (14 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:17
• Conservation: PhyloP100: 4.29
• Publications: 16 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=0.0069538355).
• BP6: Variant 2-178546480-A-T is Benign according to our data. Variant chr2-178546480-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47545.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00297 (453/152322) while in subpopulation AMR AF = 0.00582 (89/15298). AF 95% confidence interval is 0.00484. There are 8 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.94851T>A	p.Asp31617Glu	missense	Exon 342 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.89928T>A	p.Asp29976Glu	missense	Exon 292 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.87147T>A	p.Asp29049Glu	missense	Exon 291 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.94851T>A	p.Asp31617Glu	missense	Exon 342 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.94695T>A	p.Asp31565Glu	missense	Exon 340 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.94575T>A	p.Asp31525Glu	missense	Exon 340 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152204 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00288 AC: 711 AN: 246816 AF XY: 0.00285

Gnomad AFR exome AF: 0.000389

Gnomad AMR exome AF: 0.00576

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00303

Gnomad OTH exome AF: 0.00501

GnomAD4 exome AF: 0.00290 AC: 4233 AN: 1460184 Hom.: 14 Cov.: 33 AF XY: 0.00288 AC XY: 2090 AN XY: 726158

African (AFR) AF: 0.000598 AC: 20 AN: 33440

American (AMR) AF: 0.00577 AC: 258 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00961 AC: 251 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86180

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53350

Middle Eastern (MID) AF: 0.0217 AC: 125 AN: 5756

European-Non Finnish (NFE) AF: 0.00284 AC: 3149 AN: 1110744

Other (OTH) AF: 0.00544 AC: 328 AN: 60314

GnomAD4 genome AF: 0.00297 AC: 453 AN: 152322 Hom.: 8 Cov.: 32 AF XY: 0.00277 AC XY: 206 AN XY: 74476

African (AFR) AF: 0.000697 AC: 29 AN: 41578

American (AMR) AF: 0.00582 AC: 89 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4820

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10628

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00300 AC: 204 AN: 68024

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00352 Hom.: 2

Bravo AF: 0.00397

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000773 AC: 3

ESP6500EA AF: 0.00350 AC: 29

ExAC AF: 0.00285 AC: 345

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00546

EpiControl AF: 0.00524

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Cardiomyopathy (2)
-	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	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not provided (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Benign	0.94
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0070	T
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.36
Sift	Benign	0.077	T
Polyphen		1.0	D
Vest4		0.34
MutPred		0.41		Gain of catalytic residue at D29976 (P = 0.1247)
MVP		0.46
MPC		0.45
ClinPred		0.057	T
GERP RS		4.9
Mutation Taster		=84/16	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: rs72648256; hg19: chr2-179411207;