2-178735836-G-A

Variant names:

• chr2-178735836-G-A
• rs2742348
• NM_001267550.2:c.14610C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.14610C>T​(p.Ser4870Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,613,776 control chromosomes in the GnomAD database, including 801,899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73748 hom., cov: 33)
  • Exomes 𝑓: 1.0 (728151 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -0.116
• Publications: 15 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=-0.45).
• BP6: Variant 2-178735836-G-A is Benign according to our data. Variant chr2-178735836-G-A is described in ClinVar as Benign. ClinVar VariationId is 46590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.116 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.14610C>T	p.Ser4870Ser	synonymous	Exon 50 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.13659C>T	p.Ser4553Ser	synonymous	Exon 48 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.10878C>T	p.Ser3626Ser	synonymous	Exon 47 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.14610C>T	p.Ser4870Ser	synonymous	Exon 50 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.14610C>T	p.Ser4870Ser	synonymous	Exon 50 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.14334C>T	p.Ser4778Ser	synonymous	Exon 48 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.984 AC: 149695 AN: 152174 Hom.: 73691 Cov.: 33

Gnomad AFR AF: 0.944

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.991

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.996 AC: 247591 AN: 248666 AF XY: 0.997

Gnomad AFR exome AF: 0.942

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.998 AC: 1458838 AN: 1461484 Hom.: 728151 Cov.: 71 AF XY: 0.998 AC XY: 725867 AN XY: 727014

African (AFR) AF: 0.941 AC: 31494 AN: 33476

American (AMR) AF: 0.997 AC: 44564 AN: 44712

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26130 AN: 26130

East Asian (EAS) AF: 1.00 AC: 39644 AN: 39644

South Asian (SAS) AF: 1.00 AC: 86244 AN: 86254

European-Finnish (FIN) AF: 1.00 AC: 53376 AN: 53376

Middle Eastern (MID) AF: 0.997 AC: 5749 AN: 5764

European-Non Finnish (NFE) AF: 1.00 AC: 1111528 AN: 1111780

Other (OTH) AF: 0.996 AC: 60109 AN: 60348

GnomAD4 genome AF: 0.984 AC: 149811 AN: 152292 Hom.: 73748 Cov.: 33 AF XY: 0.984 AC XY: 73285 AN XY: 74458

African (AFR) AF: 0.944 AC: 39204 AN: 41538

American (AMR) AF: 0.994 AC: 15203 AN: 15294

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5181 AN: 5182

South Asian (SAS) AF: 1.00 AC: 4822 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68014 AN: 68040

Other (OTH) AF: 0.989 AC: 2090 AN: 2114

Alfa AF: 0.993 Hom.: 49285

Bravo AF: 0.981

Asia WGS AF: 0.997 AC: 3467 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.73
PhyloP100		-0.12
Mutation Taster		=86/14	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: rs2742348; hg19: chr2-179600563; COSMIC: COSV108173312; COSMIC: COSV108173312;