rs62178963

Variant names:

• chr2-178602373-C-T
• rs62178963
• NM_001267550.2:c.55029G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.55029G>A​(p.Arg18343Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,612,836 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R18343R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0088 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (93 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: 0.591
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-178602373-C-T is Benign according to our data. Variant chr2-178602373-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.591 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00879 (1336/152070) while in subpopulation NFE AF = 0.014 (951/67950). AF 95% confidence interval is 0.0133. There are 9 homozygotes in GnomAd4. There are 667 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

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.55029G>A	p.Arg18343Arg	synonymous	Exon 283 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.50106G>A	p.Arg16702Arg	synonymous	Exon 233 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.47325G>A	p.Arg15775Arg	synonymous	Exon 232 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.55029G>A	p.Arg18343Arg	synonymous	Exon 283 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.54873G>A	p.Arg18291Arg	synonymous	Exon 281 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.54753G>A	p.Arg18251Arg	synonymous	Exon 281 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00879 AC: 1336 AN: 151952 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.00624

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.00712 AC: 1768 AN: 248232 AF XY: 0.00707

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00931

GnomAD4 exome AF: 0.0103 AC: 14985 AN: 1460766 Hom.: 93 Cov.: 32 AF XY: 0.00995 AC XY: 7232 AN XY: 726662

African (AFR) AF: 0.00171 AC: 57 AN: 33424

American (AMR) AF: 0.00291 AC: 130 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 54 AN: 26108

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39534

South Asian (SAS) AF: 0.000847 AC: 73 AN: 86226

European-Finnish (FIN) AF: 0.0112 AC: 597 AN: 53378

Middle Eastern (MID) AF: 0.00521 AC: 30 AN: 5754

European-Non Finnish (NFE) AF: 0.0122 AC: 13597 AN: 1111360

Other (OTH) AF: 0.00739 AC: 446 AN: 60320

GnomAD4 genome AF: 0.00879 AC: 1336 AN: 152070 Hom.: 9 Cov.: 32 AF XY: 0.00897 AC XY: 667 AN XY: 74326

African (AFR) AF: 0.00219 AC: 91 AN: 41538

American (AMR) AF: 0.00623 AC: 95 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5138

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.0112 AC: 119 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0140 AC: 951 AN: 67950

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.0101 Hom.: 6

Bravo AF: 0.00775

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.00962

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	5	not provided (5)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	1.2
DANN	Benign	0.66
PhyloP100		0.59
Mutation Taster		=88/12	polymorphism

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: rs62178963; hg19: chr2-179467100; COSMIC: COSV60068305; COSMIC: COSV60068305;