chr2-178531627-G-A

Variant names:

• chr2-178531627-G-A
• rs3829748
• NM_001267550.2:c.104988C>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.104988C>T​(p.Val34996Val) 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 1,613,812 control chromosomes in the GnomAD database, including 22,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2311 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20378 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.114
• Publications: 19 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=-0.74).
• BP6: Variant 2-178531627-G-A is Benign according to our data. Variant chr2-178531627-G-A is described in ClinVar as Benign. ClinVar VariationId is 47681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.114 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 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.104988C>T	p.Val34996Val	synonymous	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.100065C>T	p.Val33355Val	synonymous	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.97284C>T	p.Val32428Val	synonymous	Exon 307 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.104988C>T	p.Val34996Val	synonymous	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.104832C>T	p.Val34944Val	synonymous	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.104712C>T	p.Val34904Val	synonymous	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24652 AN: 152060 Hom.: 2305 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.181 AC: 45177 AN: 248916 AF XY: 0.184

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: 0.164

GnomAD4 exome AF: 0.156 AC: 228502 AN: 1461634 Hom.: 20378 Cov.: 41 AF XY: 0.159 AC XY: 115736 AN XY: 727104

African (AFR) AF: 0.143 AC: 4792 AN: 33478

American (AMR) AF: 0.150 AC: 6688 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 4829 AN: 26136

East Asian (EAS) AF: 0.434 AC: 17223 AN: 39698

South Asian (SAS) AF: 0.250 AC: 21586 AN: 86258

European-Finnish (FIN) AF: 0.151 AC: 8073 AN: 53378

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

European-Non Finnish (NFE) AF: 0.139 AC: 154363 AN: 1111836

Other (OTH) AF: 0.169 AC: 10186 AN: 60374

GnomAD4 genome AF: 0.162 AC: 24667 AN: 152178 Hom.: 2311 Cov.: 32 AF XY: 0.166 AC XY: 12335 AN XY: 74408

African (AFR) AF: 0.145 AC: 6003 AN: 41512

American (AMR) AF: 0.135 AC: 2064 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 644 AN: 3470

East Asian (EAS) AF: 0.442 AC: 2281 AN: 5162

South Asian (SAS) AF: 0.256 AC: 1235 AN: 4822

European-Finnish (FIN) AF: 0.162 AC: 1722 AN: 10600

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9918 AN: 68002

Other (OTH) AF: 0.157 AC: 332 AN: 2110

Alfa AF: 0.151 Hom.: 3405

Bravo AF: 0.161

Asia WGS AF: 0.345 AC: 1202 AN: 3478

EpiCase AF: 0.138

EpiControl AF: 0.142

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	-0.74
CADD	Benign	0.013
DANN	Benign	0.79
PhyloP100		-0.11
Mutation Taster		=93/7	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: rs3829748; hg19: chr2-179396354; COSMIC: COSV59894492; COSMIC: COSV59894492;