rs3731746

Variant names:

• chr2-178566270-G-A
• rs3731746
• NM_001267550.2:c.79862C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178566270-G-A
• chr2-178566270-G-T

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.79862C>T​(p.Thr26621Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,613,426 control chromosomes in the GnomAD database, including 37,074 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict 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. T26621V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (5236 hom., cov: 33)
  • Exomes 𝑓: 0.19 (31838 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 3.02
• Publications: 40 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=8.6281376E-5).
• BP6: Variant 2-178566270-G-A is Benign according to our data. Variant chr2-178566270-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.596 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.79862C>T	p.Thr26621Met	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.74939C>T	p.Thr24980Met	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.72158C>T	p.Thr24053Met	missense	Exon 275 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.79862C>T	p.Thr26621Met	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.79706C>T	p.Thr26569Met	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.79586C>T	p.Thr26529Met	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36384 AN: 151866 Hom.: 5225 Cov.: 33

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.223

GnomAD2 exomes AF: 0.232 AC: 57815 AN: 248856 AF XY: 0.233

Gnomad AFR exome AF: 0.337

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.613

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.189 AC: 276307 AN: 1461442 Hom.: 31838 Cov.: 39 AF XY: 0.192 AC XY: 139377 AN XY: 727008

African (AFR) AF: 0.341 AC: 11394 AN: 33458

American (AMR) AF: 0.189 AC: 8460 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5947 AN: 26128

East Asian (EAS) AF: 0.616 AC: 24435 AN: 39686

South Asian (SAS) AF: 0.300 AC: 25865 AN: 86250

European-Finnish (FIN) AF: 0.169 AC: 9038 AN: 53386

Middle Eastern (MID) AF: 0.230 AC: 1328 AN: 5766

European-Non Finnish (NFE) AF: 0.159 AC: 176960 AN: 1111700

Other (OTH) AF: 0.213 AC: 12880 AN: 60358

GnomAD4 genome AF: 0.240 AC: 36421 AN: 151984 Hom.: 5236 Cov.: 33 AF XY: 0.243 AC XY: 18022 AN XY: 74274

African (AFR) AF: 0.337 AC: 13960 AN: 41452

American (AMR) AF: 0.186 AC: 2835 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 792 AN: 3468

East Asian (EAS) AF: 0.614 AC: 3148 AN: 5130

South Asian (SAS) AF: 0.305 AC: 1472 AN: 4824

European-Finnish (FIN) AF: 0.182 AC: 1920 AN: 10568

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11309 AN: 67968

Other (OTH) AF: 0.232 AC: 489 AN: 2110

Alfa AF: 0.194 Hom.: 12303

Bravo AF: 0.247

TwinsUK AF: 0.155 AC: 574

ALSPAC AF: 0.159 AC: 613

ESP6500AA AF: 0.327 AC: 1257

ESP6500EA AF: 0.167 AC: 1385

ExAC AF: 0.234 AC: 28299

EpiCase AF: 0.163

EpiControl AF: 0.171

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	0.073
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.87
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.000086	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.0
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.29
Sift	Benign	0.073	T
Polyphen		0.91	P
Vest4		0.23
MPC		0.30
ClinPred		0.029	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs3731746; hg19: chr2-179430997; COSMIC: COSV60115964;