rs2291311

Variant names:

• chr2-178764734-C-T
• rs2291311
• NM_001267550.2:c.9781G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178764734-C-T
• chr2-178764734-C-G

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.9781G>A​(p.Val3261Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.9 in 1,613,962 control chromosomes in the GnomAD database, including 658,565 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V3261V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.87 (57992 hom., cov: 32)
  • Exomes 𝑓: 0.90 (600573 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 1.49
• Publications: 51 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=6.5145184E-7).
• BP6: Variant 2-178764734-C-T is Benign according to our data. Variant chr2-178764734-C-T is described in ClinVar as Benign. ClinVar VariationId is 47692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.924 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.9781G>A	p.Val3261Met	missense	Exon 42 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.9781G>A	p.Val3261Met	missense	Exon 42 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.9781G>A	p.Val3261Met	missense	Exon 42 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.9781G>A	p.Val3261Met	missense	Exon 42 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.9781G>A	p.Val3261Met	missense	Exon 42 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.9505G>A	p.Val3169Met	missense	Exon 40 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132238 AN: 152066 Hom.: 57971 Cov.: 32

Gnomad AFR AF: 0.831

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 0.791

Gnomad SAS AF: 0.791

Gnomad FIN AF: 0.892

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.930

Gnomad OTH AF: 0.894

GnomAD2 exomes AF: 0.840 AC: 210661 AN: 250846 AF XY: 0.851

Gnomad AFR exome AF: 0.831

Gnomad AMR exome AF: 0.571

Gnomad ASJ exome AF: 0.914

Gnomad EAS exome AF: 0.768

Gnomad FIN exome AF: 0.892

Gnomad NFE exome AF: 0.930

Gnomad OTH exome AF: 0.871

GnomAD4 exome AF: 0.903 AC: 1320444 AN: 1461778 Hom.: 600573 Cov.: 75 AF XY: 0.902 AC XY: 656037 AN XY: 727188

African (AFR) AF: 0.830 AC: 27771 AN: 33476

American (AMR) AF: 0.586 AC: 26192 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 23962 AN: 26136

East Asian (EAS) AF: 0.791 AC: 31406 AN: 39690

South Asian (SAS) AF: 0.796 AC: 68668 AN: 86252

European-Finnish (FIN) AF: 0.889 AC: 47484 AN: 53414

Middle Eastern (MID) AF: 0.928 AC: 5327 AN: 5738

European-Non Finnish (NFE) AF: 0.931 AC: 1035537 AN: 1111968

Other (OTH) AF: 0.896 AC: 54097 AN: 60388

GnomAD4 genome AF: 0.869 AC: 132299 AN: 152184 Hom.: 57992 Cov.: 32 AF XY: 0.863 AC XY: 64240 AN XY: 74398

African (AFR) AF: 0.830 AC: 34455 AN: 41502

American (AMR) AF: 0.718 AC: 10969 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 3189 AN: 3472

East Asian (EAS) AF: 0.790 AC: 4088 AN: 5174

South Asian (SAS) AF: 0.792 AC: 3814 AN: 4818

European-Finnish (FIN) AF: 0.892 AC: 9443 AN: 10592

Middle Eastern (MID) AF: 0.949 AC: 279 AN: 294

European-Non Finnish (NFE) AF: 0.930 AC: 63300 AN: 68028

Other (OTH) AF: 0.896 AC: 1894 AN: 2114

Alfa AF: 0.905 Hom.: 267890

Bravo AF: 0.853

TwinsUK AF: 0.931 AC: 3453

ALSPAC AF: 0.929 AC: 3582

ESP6500AA AF: 0.827 AC: 3643

ESP6500EA AF: 0.932 AC: 8017

ExAC AF: 0.850 AC: 103172

Asia WGS AF: 0.798 AC: 2777 AN: 3476

EpiCase AF: 0.935

EpiControl AF: 0.932

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	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	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.89
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	6.5e-7	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.23
Sift	Benign	0.16	T
Sift4G	Benign	0.090	T
Polyphen		0.99	D
Vest4		0.066
MPC		0.33
ClinPred		0.014	T
GERP RS		4.8
Mutation Taster		=95/5	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: rs2291311; hg19: chr2-179629461; COSMIC: COSV59876288; COSMIC: COSV59876288;