rs3731749

Variant names:

• chr2-178541464-C-T
• rs3731749
• NM_001267550.2:c.97613G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178541464-C-T
• chr2-178541464-C-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.97613G>A​(p.Arg32538His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,612,826 control chromosomes in the GnomAD database, including 21,855 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32538C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1972 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19883 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 7.90
• Publications: 35 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]

ENSG00000270956 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025874078).
• BP6: Variant 2-178541464-C-T is Benign according to our data. Variant chr2-178541464-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.426 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.97613G>A	p.Arg32538His	missense	Exon 350 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.92690G>A	p.Arg30897His	missense	Exon 300 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.89909G>A	p.Arg29970His	missense	Exon 299 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.97613G>A	p.Arg32538His	missense	Exon 350 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.97457G>A	p.Arg32486His	missense	Exon 348 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.97337G>A	p.Arg32446His	missense	Exon 348 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21507 AN: 151934 Hom.: 1966 Cov.: 32

Gnomad AFR AF: 0.0754

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.175 AC: 43495 AN: 248024 AF XY: 0.179

Gnomad AFR exome AF: 0.0703

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.429

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.154 AC: 224610 AN: 1460776 Hom.: 19883 Cov.: 32 AF XY: 0.157 AC XY: 113946 AN XY: 726608

African (AFR) AF: 0.0712 AC: 2382 AN: 33444

American (AMR) AF: 0.145 AC: 6485 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4380 AN: 26118

East Asian (EAS) AF: 0.434 AC: 17186 AN: 39640

South Asian (SAS) AF: 0.250 AC: 21577 AN: 86168

European-Finnish (FIN) AF: 0.151 AC: 8062 AN: 53344

Middle Eastern (MID) AF: 0.126 AC: 723 AN: 5760

European-Non Finnish (NFE) AF: 0.139 AC: 154027 AN: 1111332

Other (OTH) AF: 0.162 AC: 9788 AN: 60316

GnomAD4 genome AF: 0.142 AC: 21517 AN: 152050 Hom.: 1972 Cov.: 32 AF XY: 0.146 AC XY: 10866 AN XY: 74290

African (AFR) AF: 0.0752 AC: 3122 AN: 41504

American (AMR) AF: 0.128 AC: 1949 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 591 AN: 3470

East Asian (EAS) AF: 0.441 AC: 2265 AN: 5140

South Asian (SAS) AF: 0.256 AC: 1232 AN: 4818

European-Finnish (FIN) AF: 0.163 AC: 1717 AN: 10556

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9889 AN: 67970

Other (OTH) AF: 0.135 AC: 285 AN: 2110

Alfa AF: 0.149 Hom.: 4755

Bravo AF: 0.137

TwinsUK AF: 0.133 AC: 494

ALSPAC AF: 0.140 AC: 538

ESP6500AA AF: 0.0732 AC: 289

ESP6500EA AF: 0.145 AC: 1206

ExAC AF: 0.175 AC: 21137

Asia WGS AF: 0.341 AC: 1188 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.140

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	not provided (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	0.33
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.34
MPC		0.52
ClinPred		0.0075	T
GERP RS		5.7
Mutation Taster		=96/4	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: rs3731749; hg19: chr2-179406191; COSMIC: COSV59894639; COSMIC: COSV59894639;