rs55847232

Variant names:

• chr2-178636063-A-G
• rs55847232
• NM_001267550.2:c.41508T>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.41508T>C​(p.Ala13836Ala) 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 1,613,210 control chromosomes in the GnomAD database, including 744 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 (74 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: 0.0180
• Publications: 6 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=-0.81).
• BP6: Variant 2-178636063-A-G is Benign according to our data. Variant chr2-178636063-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.018 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0875 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.41508T>C	p.Ala13836Ala	synonymous	Exon 226 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.36585T>C	p.Ala12195Ala	synonymous	Exon 176 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.33804T>C	p.Ala11268Ala	synonymous	Exon 175 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.41508T>C	p.Ala13836Ala	synonymous	Exon 226 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.41352T>C	p.Ala13784Ala	synonymous	Exon 224 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.41232T>C	p.Ala13744Ala	synonymous	Exon 224 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3532 AN: 152000 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.00493

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0942

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0451

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0235

GnomAD2 exomes AF: 0.0327 AC: 8117 AN: 248294 AF XY: 0.0319

Gnomad AFR exome AF: 0.00530

Gnomad AMR exome AF: 0.0343

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0249

Gnomad OTH exome AF: 0.0305

GnomAD4 exome AF: 0.0260 AC: 38009 AN: 1461092 Hom.: 670 Cov.: 32 AF XY: 0.0261 AC XY: 18997 AN XY: 726828

African (AFR) AF: 0.00469 AC: 157 AN: 33440

American (AMR) AF: 0.0326 AC: 1456 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 396 AN: 26118

East Asian (EAS) AF: 0.0926 AC: 3664 AN: 39570

South Asian (SAS) AF: 0.0282 AC: 2435 AN: 86226

European-Finnish (FIN) AF: 0.0490 AC: 2616 AN: 53382

Middle Eastern (MID) AF: 0.0144 AC: 83 AN: 5762

European-Non Finnish (NFE) AF: 0.0230 AC: 25605 AN: 1111546

Other (OTH) AF: 0.0265 AC: 1597 AN: 60340

GnomAD4 genome AF: 0.0232 AC: 3532 AN: 152118 Hom.: 74 Cov.: 32 AF XY: 0.0239 AC XY: 1780 AN XY: 74346

African (AFR) AF: 0.00491 AC: 204 AN: 41540

American (AMR) AF: 0.0251 AC: 383 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.0945 AC: 485 AN: 5134

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

European-Finnish (FIN) AF: 0.0451 AC: 478 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0247 AC: 1682 AN: 67966

Other (OTH) AF: 0.0232 AC: 49 AN: 2108

Alfa AF: 0.0214 Hom.: 22

Bravo AF: 0.0210

Asia WGS AF: 0.0490 AC: 169 AN: 3478

EpiCase AF: 0.0226

EpiControl AF: 0.0241

ClinVar

ClinVar submissions

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	-0.81
CADD	Benign	0.60
DANN	Benign	0.53
PhyloP100		0.018
Mutation Taster		=97/3	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: rs55847232; hg19: chr2-179500790; COSMIC: COSV107417831; COSMIC: COSV107417831;