rs2291312

Variant names:

• chr2-178766487-T-C
• rs2291312
• NM_001267550.2:c.9597A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178766487-T-C
• chr2-178766487-T-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.9597A>G​(p.Glu3199Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0949 in 1,613,924 control chromosomes in the GnomAD database, including 11,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1301 hom., cov: 32)
  • Exomes 𝑓: 0.094 (10489 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.651
• 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=-0.57).
• BP6: Variant 2-178766487-T-C is Benign according to our data. Variant chr2-178766487-T-C is described in ClinVar as Benign. ClinVar VariationId is 47661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.651 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.269 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.9597A>G	p.Glu3199Glu	synonymous	Exon 41 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.9597A>G	p.Glu3199Glu	synonymous	Exon 41 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.9597A>G	p.Glu3199Glu	synonymous	Exon 41 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.9597A>G	p.Glu3199Glu	synonymous	Exon 41 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.9597A>G	p.Glu3199Glu	synonymous	Exon 41 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.9321A>G	p.Glu3107Glu	synonymous	Exon 39 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16037 AN: 152118 Hom.: 1288 Cov.: 32

Gnomad AFR AF: 0.0820

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.0815

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.0865

GnomAD2 exomes AF: 0.154 AC: 38565 AN: 251170 AF XY: 0.144

Gnomad AFR exome AF: 0.0821

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.0866

Gnomad EAS exome AF: 0.231

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0691

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.0937 AC: 137025 AN: 1461688 Hom.: 10489 Cov.: 33 AF XY: 0.0953 AC XY: 69294 AN XY: 727150

African (AFR) AF: 0.0785 AC: 2629 AN: 33478

American (AMR) AF: 0.411 AC: 18359 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0832 AC: 2173 AN: 26130

East Asian (EAS) AF: 0.209 AC: 8273 AN: 39678

South Asian (SAS) AF: 0.203 AC: 17523 AN: 86254

European-Finnish (FIN) AF: 0.111 AC: 5928 AN: 53420

Middle Eastern (MID) AF: 0.0667 AC: 385 AN: 5768

European-Non Finnish (NFE) AF: 0.0682 AC: 75869 AN: 1111854

Other (OTH) AF: 0.0975 AC: 5886 AN: 60390

GnomAD4 genome AF: 0.105 AC: 16057 AN: 152236 Hom.: 1301 Cov.: 32 AF XY: 0.112 AC XY: 8356 AN XY: 74420

African (AFR) AF: 0.0819 AC: 3403 AN: 41548

American (AMR) AF: 0.276 AC: 4217 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0815 AC: 283 AN: 3472

East Asian (EAS) AF: 0.210 AC: 1086 AN: 5178

South Asian (SAS) AF: 0.207 AC: 998 AN: 4816

European-Finnish (FIN) AF: 0.109 AC: 1151 AN: 10596

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0688 AC: 4683 AN: 68018

Other (OTH) AF: 0.0847 AC: 179 AN: 2114

Alfa AF: 0.0887 Hom.: 3072

Bravo AF: 0.118

Asia WGS AF: 0.194 AC: 671 AN: 3478

EpiCase AF: 0.0640

EpiControl AF: 0.0671

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	-0.57
CADD	Benign	7.6
DANN	Benign	0.64
PhyloP100		0.65
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: rs2291312; hg19: chr2-179631214; COSMIC: COSV60092695; COSMIC: COSV60092695;