chr2-178720539-C-T

Variant names:

• chr2-178720539-C-T
• rs2562831
• NM_001267550.2:c.23223G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.23223G>A​(p.Gln7741Gln) 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 1,613,548 control chromosomes in the GnomAD database, including 801,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73738 hom., cov: 32)
  • Exomes 𝑓: 1.0 (728085 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 0.658
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-178720539-C-T is Benign according to our data. Variant chr2-178720539-C-T is described in ClinVar as Benign. ClinVar VariationId is 46714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.658 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.23223G>A	p.Gln7741Gln	synonymous	Exon 80 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.22272G>A	p.Gln7424Gln	synonymous	Exon 78 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.19491G>A	p.Gln6497Gln	synonymous	Exon 77 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.23223G>A	p.Gln7741Gln	synonymous	Exon 80 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.23223G>A	p.Gln7741Gln	synonymous	Exon 80 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.22947G>A	p.Gln7649Gln	synonymous	Exon 78 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.984 AC: 149665 AN: 152136 Hom.: 73681 Cov.: 32

Gnomad AFR AF: 0.944

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.993

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: 247332 AN: 248384 AF XY: 0.997

Gnomad AFR exome AF: 0.943

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: 1458675 AN: 1461294 Hom.: 728085 Cov.: 64 AF XY: 0.998 AC XY: 725778 AN XY: 726914

African (AFR) AF: 0.942 AC: 31493 AN: 33446

American (AMR) AF: 0.997 AC: 44560 AN: 44708

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26122 AN: 26122

East Asian (EAS) AF: 1.00 AC: 39674 AN: 39674

South Asian (SAS) AF: 1.00 AC: 86230 AN: 86242

European-Finnish (FIN) AF: 1.00 AC: 53374 AN: 53374

Middle Eastern (MID) AF: 0.997 AC: 5744 AN: 5760

European-Non Finnish (NFE) AF: 1.00 AC: 1111378 AN: 1111626

Other (OTH) AF: 0.996 AC: 60100 AN: 60342

GnomAD4 genome AF: 0.984 AC: 149781 AN: 152254 Hom.: 73738 Cov.: 32 AF XY: 0.984 AC XY: 73257 AN XY: 74432

African (AFR) AF: 0.944 AC: 39252 AN: 41560

American (AMR) AF: 0.993 AC: 15177 AN: 15288

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

East Asian (EAS) AF: 1.00 AC: 5167 AN: 5168

South Asian (SAS) AF: 1.00 AC: 4816 AN: 4818

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

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

European-Non Finnish (NFE) AF: 1.00 AC: 67980 AN: 68004

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

Alfa AF: 0.994 Hom.: 103726

Bravo AF: 0.981

Asia WGS AF: 0.997 AC: 3465 AN: 3476

EpiCase AF: 1.00

EpiControl AF: 0.999

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	-0.53
CADD	Benign	2.5
DANN	Benign	0.51
PhyloP100		0.66
Mutation Taster		=85/15	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: rs2562831; hg19: chr2-179585266; COSMIC: COSV108173310; COSMIC: COSV108173310;