rs3731748

Variant names:

• chr2-178548383-G-A
• rs3731748
• NM_001267550.2:c.93243C>T

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.93243C>T​(p.Ala31081Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,564 control chromosomes in the GnomAD database, including 22,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2329 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20578 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.178
• Publications: 20 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=-0.75).
• BP6: Variant 2-178548383-G-A is Benign according to our data. Variant chr2-178548383-G-A is described in ClinVar as Benign. ClinVar VariationId is 47530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.178 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.428 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.93243C>T	p.Ala31081Ala	synonymous	Exon 339 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.88320C>T	p.Ala29440Ala	synonymous	Exon 289 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.85539C>T	p.Ala28513Ala	synonymous	Exon 288 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.93243C>T	p.Ala31081Ala	synonymous	Exon 339 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.93087C>T	p.Ala31029Ala	synonymous	Exon 337 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.92967C>T	p.Ala30989Ala	synonymous	Exon 337 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24696 AN: 151878 Hom.: 2323 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.183 AC: 45432 AN: 248198 AF XY: 0.186

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.430

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.157 AC: 229267 AN: 1461568 Hom.: 20578 Cov.: 35 AF XY: 0.160 AC XY: 116291 AN XY: 727068

African (AFR) AF: 0.143 AC: 4790 AN: 33474

American (AMR) AF: 0.150 AC: 6694 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 4824 AN: 26128

East Asian (EAS) AF: 0.434 AC: 17216 AN: 39700

South Asian (SAS) AF: 0.259 AC: 22323 AN: 86258

European-Finnish (FIN) AF: 0.151 AC: 8076 AN: 53350

Middle Eastern (MID) AF: 0.132 AC: 762 AN: 5768

European-Non Finnish (NFE) AF: 0.139 AC: 154368 AN: 1111798

Other (OTH) AF: 0.169 AC: 10214 AN: 60370

GnomAD4 genome AF: 0.163 AC: 24710 AN: 151996 Hom.: 2329 Cov.: 32 AF XY: 0.167 AC XY: 12380 AN XY: 74288

African (AFR) AF: 0.145 AC: 6003 AN: 41474

American (AMR) AF: 0.135 AC: 2061 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 643 AN: 3468

East Asian (EAS) AF: 0.443 AC: 2276 AN: 5140

South Asian (SAS) AF: 0.269 AC: 1294 AN: 4804

European-Finnish (FIN) AF: 0.163 AC: 1722 AN: 10582

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9911 AN: 67954

Other (OTH) AF: 0.158 AC: 333 AN: 2112

Alfa AF: 0.152 Hom.: 4279

Bravo AF: 0.161

Asia WGS AF: 0.347 AC: 1208 AN: 3476

EpiCase AF: 0.138

EpiControl AF: 0.142

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	-0.75
CADD	Benign	0.20
DANN	Benign	0.85
PhyloP100		0.18
Mutation Taster		=99/1	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: rs3731748; hg19: chr2-179413110; COSMIC: COSV59894670; COSMIC: COSV59894670;