rs3731744

Variant names:

• chr2-178567070-A-T
• rs3731744
• NM_001267550.2:c.79062T>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.79062T>A​(p.Gly26354Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0334 in 1,613,528 control chromosomes in the GnomAD database, including 1,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G26354G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.058 (461 hom., cov: 33)
  • Exomes 𝑓: 0.031 (1528 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -0.131
• Publications: 6 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=-0.6).
• BP6: Variant 2-178567070-A-T is Benign according to our data. Variant chr2-178567070-A-T is described in ClinVar as Benign. ClinVar VariationId is 47370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.131 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 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.79062T>A	p.Gly26354Gly	synonymous	Exon 326 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.74139T>A	p.Gly24713Gly	synonymous	Exon 276 of 313	NP_001243779.1
	TTN	NM_133378.4		c.71358T>A	p.Gly23786Gly	synonymous	Exon 275 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.79062T>A	p.Gly26354Gly	synonymous	Exon 326 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.78906T>A	p.Gly26302Gly	synonymous	Exon 324 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.78786T>A	p.Gly26262Gly	synonymous	Exon 324 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0582 AC: 8855 AN: 152050 Hom.: 460 Cov.: 33

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.0480

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.0627

GnomAD2 exomes AF: 0.0458 AC: 11386 AN: 248418 AF XY: 0.0450

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0337

Gnomad ASJ exome AF: 0.0421

Gnomad EAS exome AF: 0.183

Gnomad FIN exome AF: 0.0204

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0430

GnomAD4 exome AF: 0.0308 AC: 44969 AN: 1461360 Hom.: 1528 Cov.: 37 AF XY: 0.0309 AC XY: 22477 AN XY: 726976

African (AFR) AF: 0.125 AC: 4185 AN: 33448

American (AMR) AF: 0.0362 AC: 1617 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 1121 AN: 26126

East Asian (EAS) AF: 0.182 AC: 7223 AN: 39684

South Asian (SAS) AF: 0.0497 AC: 4288 AN: 86246

European-Finnish (FIN) AF: 0.0179 AC: 956 AN: 53396

Middle Eastern (MID) AF: 0.0988 AC: 569 AN: 5760

European-Non Finnish (NFE) AF: 0.0203 AC: 22592 AN: 1111634

Other (OTH) AF: 0.0401 AC: 2418 AN: 60348

GnomAD4 genome AF: 0.0583 AC: 8874 AN: 152168 Hom.: 461 Cov.: 33 AF XY: 0.0589 AC XY: 4385 AN XY: 74388

African (AFR) AF: 0.124 AC: 5160 AN: 41528

American (AMR) AF: 0.0454 AC: 693 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 148 AN: 3470

East Asian (EAS) AF: 0.171 AC: 879 AN: 5144

South Asian (SAS) AF: 0.0486 AC: 235 AN: 4832

European-Finnish (FIN) AF: 0.0193 AC: 205 AN: 10618

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0205 AC: 1394 AN: 67988

Other (OTH) AF: 0.0630 AC: 133 AN: 2112

Alfa AF: 0.0318 Hom.: 51

Bravo AF: 0.0634

Asia WGS AF: 0.102 AC: 352 AN: 3478

EpiCase AF: 0.0252

EpiControl AF: 0.0289

ClinVar

ClinVar submissions as Germline

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	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
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.15
DANN	Benign	0.71
PhyloP100		-0.13
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: rs3731744; hg19: chr2-179431797;