rs72648257

Variant names:

• chr2-178546284-T-C
• rs72648257
• NM_001267550.2:c.95047A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178546284-T-C
• chr2-178546284-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.95047A>G​(p.Ser31683Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0229 in 1,613,852 control chromosomes in the GnomAD database, including 526 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (50 hom., cov: 33)
  • Exomes 𝑓: 0.023 (476 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 4.93
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042873025).
• BP6: Variant 2-178546284-T-C is Benign according to our data. Variant chr2-178546284-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0553 is higher than 0.05.

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.95047A>G	p.Ser31683Gly	missense	Exon 342 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.90124A>G	p.Ser30042Gly	missense	Exon 292 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.87343A>G	p.Ser29115Gly	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.95047A>G	p.Ser31683Gly	missense	Exon 342 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.94891A>G	p.Ser31631Gly	missense	Exon 340 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.94771A>G	p.Ser31591Gly	missense	Exon 340 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3077 AN: 152216 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0607

Gnomad SAS AF: 0.00806

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0260 AC: 6478 AN: 248750 AF XY: 0.0246

Gnomad AFR exome AF: 0.00491

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.0617

Gnomad FIN exome AF: 0.0472

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0258

GnomAD4 exome AF: 0.0232 AC: 33883 AN: 1461518 Hom.: 476 Cov.: 33 AF XY: 0.0228 AC XY: 16570 AN XY: 727038

African (AFR) AF: 0.00409 AC: 137 AN: 33472

American (AMR) AF: 0.0322 AC: 1440 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 374 AN: 26130

East Asian (EAS) AF: 0.0634 AC: 2515 AN: 39694

South Asian (SAS) AF: 0.00676 AC: 583 AN: 86242

European-Finnish (FIN) AF: 0.0483 AC: 2577 AN: 53396

Middle Eastern (MID) AF: 0.00990 AC: 57 AN: 5760

European-Non Finnish (NFE) AF: 0.0224 AC: 24884 AN: 1111738

Other (OTH) AF: 0.0218 AC: 1316 AN: 60366

GnomAD4 genome AF: 0.0202 AC: 3074 AN: 152334 Hom.: 50 Cov.: 33 AF XY: 0.0206 AC XY: 1538 AN XY: 74496

African (AFR) AF: 0.00447 AC: 186 AN: 41576

American (AMR) AF: 0.0218 AC: 334 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3468

East Asian (EAS) AF: 0.0609 AC: 315 AN: 5176

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4832

European-Finnish (FIN) AF: 0.0447 AC: 475 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0234 AC: 1592 AN: 68026

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0229 Hom.: 167

Bravo AF: 0.0185

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0244 AC: 94

ESP6500AA AF: 0.00512 AC: 20

ESP6500EA AF: 0.0205 AC: 170

ExAC AF: 0.0262 AC: 3162

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.0202

EpiControl AF: 0.0218

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.92
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.78	N
PhyloP100		4.9
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.28
Sift	Benign	0.24	T
Polyphen		0.98	D
Vest4		0.30
MPC		0.28
ClinPred		0.025	T
GERP RS		5.7
Mutation Taster		=98/2	polymorphism (auto)

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: rs72648257; hg19: chr2-179411011; COSMIC: COSV60085005; COSMIC: COSV60085005;