rs2857265

Variant names:

• chr2-178534096-G-A
• rs2857265
• NM_001267550.2:c.102519C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178534096-G-A
• chr2-178534096-G-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.102519C>T​(p.Gly34173Gly) 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 1,613,738 control chromosomes in the GnomAD database, including 22,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2315 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20396 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.352
• 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=-0.79).
• BP6: Variant 2-178534096-G-A is Benign according to our data. Variant chr2-178534096-G-A is described in ClinVar as Benign. ClinVar VariationId is 47650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.352 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.102519C>T	p.Gly34173Gly	synonymous	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.97596C>T	p.Gly32532Gly	synonymous	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.94815C>T	p.Gly31605Gly	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.102519C>T	p.Gly34173Gly	synonymous	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.102363C>T	p.Gly34121Gly	synonymous	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.102243C>T	p.Gly34081Gly	synonymous	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24647 AN: 151992 Hom.: 2309 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.182 AC: 45212 AN: 248860 AF XY: 0.185

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: 228687 AN: 1461628 Hom.: 20396 Cov.: 40 AF XY: 0.159 AC XY: 115827 AN XY: 727108

African (AFR) AF: 0.143 AC: 4790 AN: 33472

American (AMR) AF: 0.150 AC: 6686 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 4827 AN: 26134

East Asian (EAS) AF: 0.434 AC: 17210 AN: 39698

South Asian (SAS) AF: 0.250 AC: 21584 AN: 86256

European-Finnish (FIN) AF: 0.151 AC: 8081 AN: 53398

Middle Eastern (MID) AF: 0.132 AC: 761 AN: 5768

European-Non Finnish (NFE) AF: 0.139 AC: 154565 AN: 1111808

Other (OTH) AF: 0.169 AC: 10183 AN: 60372

GnomAD4 genome AF: 0.162 AC: 24662 AN: 152110 Hom.: 2315 Cov.: 32 AF XY: 0.166 AC XY: 12325 AN XY: 74354

African (AFR) AF: 0.145 AC: 6007 AN: 41496

American (AMR) AF: 0.135 AC: 2065 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 644 AN: 3468

East Asian (EAS) AF: 0.442 AC: 2275 AN: 5148

South Asian (SAS) AF: 0.256 AC: 1233 AN: 4824

European-Finnish (FIN) AF: 0.163 AC: 1721 AN: 10576

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

European-Non Finnish (NFE) AF: 0.146 AC: 9917 AN: 67994

Other (OTH) AF: 0.157 AC: 332 AN: 2112

Alfa AF: 0.152 Hom.: 2026

Bravo AF: 0.161

Asia WGS AF: 0.345 AC: 1201 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	-0.79
CADD	Benign	0.018
DANN	Benign	0.82
PhyloP100		-0.35
Mutation Taster		=84/16	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: rs2857265; hg19: chr2-179398823; COSMIC: COSV59894552; COSMIC: COSV59894552;