rs2303836

Variant names:

• chr2-178593275-G-A
• rs2303836
• NM_001267550.2:c.58933C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178593275-G-A
• chr2-178593275-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.58933C>T​(p.Leu19645Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0109 in 1,613,362 control chromosomes in the GnomAD database, including 1,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (156 hom., cov: 32)
  • Exomes 𝑓: 0.010 (1329 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 3.97
• Publications: 10 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-178593275-G-A is Benign according to our data. Variant chr2-178593275-G-A is described in ClinVar as Benign. ClinVar VariationId is 47142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.104 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.58933C>T	p.Leu19645Leu	synonymous	Exon 299 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.54010C>T	p.Leu18004Leu	synonymous	Exon 249 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.51229C>T	p.Leu17077Leu	synonymous	Exon 248 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.58933C>T	p.Leu19645Leu	synonymous	Exon 299 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.58777C>T	p.Leu19593Leu	synonymous	Exon 297 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.58657C>T	p.Leu19553Leu	synonymous	Exon 297 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2324 AN: 152020 Hom.: 154 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0719

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0378 AC: 9404 AN: 248544 AF XY: 0.0293

Gnomad AFR exome AF: 0.00323

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.0659

Gnomad FIN exome AF: 0.00209

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0104 AC: 15238 AN: 1461224 Hom.: 1329 Cov.: 35 AF XY: 0.00939 AC XY: 6824 AN XY: 726886

African (AFR) AF: 0.00242 AC: 81 AN: 33452

American (AMR) AF: 0.207 AC: 9270 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26116

East Asian (EAS) AF: 0.0866 AC: 3432 AN: 39620

South Asian (SAS) AF: 0.00492 AC: 424 AN: 86238

European-Finnish (FIN) AF: 0.00221 AC: 118 AN: 53402

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.00114 AC: 1266 AN: 1111592

Other (OTH) AF: 0.0101 AC: 608 AN: 60352

GnomAD4 genome AF: 0.0153 AC: 2335 AN: 152138 Hom.: 156 Cov.: 32 AF XY: 0.0163 AC XY: 1215 AN XY: 74362

African (AFR) AF: 0.00286 AC: 119 AN: 41546

American (AMR) AF: 0.109 AC: 1658 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.0721 AC: 370 AN: 5134

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4822

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 67984

Other (OTH) AF: 0.0161 AC: 34 AN: 2110

Alfa AF: 0.0132 Hom.: 303

Bravo AF: 0.0275

Asia WGS AF: 0.0380 AC: 131 AN: 3476

EpiCase AF: 0.000709

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	1.8
DANN	Benign	0.84
PhyloP100		4.0
Mutation Taster		=76/24	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2303836; hg19: chr2-179458002; COSMIC: COSV59948251; COSMIC: COSV59948251;