chr2-178620872-A-G

Variant names:

• chr2-178620872-A-G
• rs2303829
• NM_001267550.2:c.45738T>C

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.45738T>C​(p.Ala15246Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,612,574 control chromosomes in the GnomAD database, including 743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (73 hom., cov: 32)
  • Exomes 𝑓: 0.026 (670 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 0.403
• Publications: 9 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=-0.56).
• BP6: Variant 2-178620872-A-G is Benign according to our data. Variant chr2-178620872-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.403 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0891 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.45738T>C	p.Ala15246Ala	synonymous	Exon 247 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.40815T>C	p.Ala13605Ala	synonymous	Exon 197 of 313	NP_001243779.1
	TTN	NM_133378.4		c.38034T>C	p.Ala12678Ala	synonymous	Exon 196 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.45738T>C	p.Ala15246Ala	synonymous	Exon 247 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.45582T>C	p.Ala15194Ala	synonymous	Exon 245 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.45462T>C	p.Ala15154Ala	synonymous	Exon 245 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3528 AN: 151882 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.00483

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0959

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0328 AC: 8118 AN: 247420 AF XY: 0.0320

Gnomad AFR exome AF: 0.00524

Gnomad AMR exome AF: 0.0345

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.0474

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0307

GnomAD4 exome AF: 0.0260 AC: 38042 AN: 1460574 Hom.: 670 Cov.: 32 AF XY: 0.0262 AC XY: 19018 AN XY: 726590

African (AFR) AF: 0.00455 AC: 152 AN: 33404

American (AMR) AF: 0.0328 AC: 1466 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 396 AN: 26088

East Asian (EAS) AF: 0.0927 AC: 3670 AN: 39574

South Asian (SAS) AF: 0.0283 AC: 2441 AN: 86218

European-Finnish (FIN) AF: 0.0491 AC: 2618 AN: 53366

Middle Eastern (MID) AF: 0.0144 AC: 83 AN: 5754

European-Non Finnish (NFE) AF: 0.0231 AC: 25617 AN: 1111226

Other (OTH) AF: 0.0265 AC: 1599 AN: 60304

GnomAD4 genome AF: 0.0232 AC: 3528 AN: 152000 Hom.: 73 Cov.: 32 AF XY: 0.0239 AC XY: 1776 AN XY: 74296

African (AFR) AF: 0.00482 AC: 200 AN: 41532

American (AMR) AF: 0.0251 AC: 383 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3464

East Asian (EAS) AF: 0.0962 AC: 492 AN: 5116

South Asian (SAS) AF: 0.0315 AC: 152 AN: 4820

European-Finnish (FIN) AF: 0.0449 AC: 476 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0247 AC: 1677 AN: 67882

Other (OTH) AF: 0.0232 AC: 49 AN: 2112

Alfa AF: 0.0224 Hom.: 32

Bravo AF: 0.0210

Asia WGS AF: 0.0490 AC: 170 AN: 3476

EpiCase AF: 0.0226

EpiControl AF: 0.0242

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.6
DANN	Benign	0.80
PhyloP100		0.40
Mutation Taster		=79/21	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: rs2303829; hg19: chr2-179485599; COSMIC: COSV60187926; COSMIC: COSV60187926;