rs56142888

Variant names:

• chr2-178773134-C-G
• rs56142888
• NM_001267550.2:c.7830G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178773134-C-G
• chr2-178773134-C-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.7830G>C​(p.Met2610Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0524 in 1,613,764 control chromosomes in the GnomAD database, including 3,776 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (364 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3412 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 0.689
• Publications: 19 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=0.0010922849).
• BP6: Variant 2-178773134-C-G is Benign according to our data. Variant chr2-178773134-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 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.7830G>C	p.Met2610Ile	missense	Exon 33 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.7830G>C	p.Met2610Ile	missense	Exon 33 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.7830G>C	p.Met2610Ile	missense	Exon 33 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.7830G>C	p.Met2610Ile	missense	Exon 33 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.7830G>C	p.Met2610Ile	missense	Exon 33 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.7554G>C	p.Met2518Ile	missense	Exon 31 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7581 AN: 152156 Hom.: 363 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0463

GnomAD2 exomes AF: 0.0786 AC: 19703 AN: 250578 AF XY: 0.0695

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.0484

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0444

Gnomad OTH exome AF: 0.0662

GnomAD4 exome AF: 0.0527 AC: 77008 AN: 1461490 Hom.: 3412 Cov.: 32 AF XY: 0.0509 AC XY: 36982 AN XY: 727032

African (AFR) AF: 0.00938 AC: 314 AN: 33472

American (AMR) AF: 0.227 AC: 10160 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0473 AC: 1237 AN: 26126

East Asian (EAS) AF: 0.189 AC: 7505 AN: 39638

South Asian (SAS) AF: 0.0197 AC: 1696 AN: 86224

European-Finnish (FIN) AF: 0.0546 AC: 2915 AN: 53404

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5764

European-Non Finnish (NFE) AF: 0.0450 AC: 49985 AN: 1111806

Other (OTH) AF: 0.0514 AC: 3103 AN: 60380

GnomAD4 genome AF: 0.0498 AC: 7584 AN: 152274 Hom.: 364 Cov.: 32 AF XY: 0.0514 AC XY: 3827 AN XY: 74440

African (AFR) AF: 0.0116 AC: 481 AN: 41578

American (AMR) AF: 0.138 AC: 2114 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 170 AN: 3472

East Asian (EAS) AF: 0.184 AC: 954 AN: 5186

South Asian (SAS) AF: 0.0215 AC: 104 AN: 4828

European-Finnish (FIN) AF: 0.0513 AC: 544 AN: 10604

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0452 AC: 3073 AN: 68008

Other (OTH) AF: 0.0449 AC: 95 AN: 2116

Alfa AF: 0.0485 Hom.: 197

Bravo AF: 0.0607

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0493 AC: 190

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.0433 AC: 372

ExAC AF: 0.0712 AC: 8641

Asia WGS AF: 0.0740 AC: 256 AN: 3478

EpiCase AF: 0.0405

EpiControl AF: 0.0432

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	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Benign	0.92
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.69
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.11
Sift	Benign	0.34	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.44		Gain of catalytic residue at L2615 (P = 0.0744)
MPC		0.093
ClinPred		0.0049	T
GERP RS		4.7
Mutation Taster		=94/6	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: rs56142888; hg19: chr2-179637861; COSMIC: COSV104640960; COSMIC: COSV104640960;