rs55847238

Variant names:

• chr2-178575317-C-T
• rs55847238
• NM_001267550.2:c.70815G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001267550.2(TTN):​c.70815G>A​(p.Val23605Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,518 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (11 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:19
• Conservation: PhyloP100: -0.0580
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-178575317-C-T is Benign according to our data. Variant chr2-178575317-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47292.
• BP7: Synonymous conserved (PhyloP=-0.058 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00219 (333/152248) while in subpopulation NFE AF = 0.00384 (261/67992). AF 95% confidence interval is 0.00346. There are 1 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

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.70815G>A	p.Val23605Val	synonymous	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.65892G>A	p.Val21964Val	synonymous	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.63111G>A	p.Val21037Val	synonymous	Exon 275 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.70815G>A	p.Val23605Val	synonymous	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.70659G>A	p.Val23553Val	synonymous	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.70539G>A	p.Val23513Val	synonymous	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00234 AC: 580 AN: 248344 AF XY: 0.00238

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00604

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00299 AC: 4375 AN: 1461270 Hom.: 11 Cov.: 36 AF XY: 0.00300 AC XY: 2184 AN XY: 726920

African (AFR) AF: 0.000209 AC: 7 AN: 33462

American (AMR) AF: 0.000604 AC: 27 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86248

European-Finnish (FIN) AF: 0.00678 AC: 362 AN: 53396

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.00345 AC: 3835 AN: 1111658

Other (OTH) AF: 0.00197 AC: 119 AN: 60358

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74412

African (AFR) AF: 0.000385 AC: 16 AN: 41568

American (AMR) AF: 0.000458 AC: 7 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00442 AC: 47 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00384 AC: 261 AN: 67992

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00267 Hom.: 3

Bravo AF: 0.00167

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	not provided (5)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	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)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.28
DANN	Benign	0.82
PhyloP100		-0.058
Mutation Taster		=91/9	polymorphism

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: rs55847238; hg19: chr2-179440044;