rs113391261

Variant names:

• chr2-178718729-G-A
• rs113391261
• NM_001267550.2:c.24471C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.24471C>T​(p.Gly8157Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000957 in 1,613,744 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (12 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 0.282
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 2-178718729-G-A is Benign according to our data. Variant chr2-178718729-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00513 (781/152234) while in subpopulation AFR AF = 0.0178 (739/41552). AF 95% confidence interval is 0.0167. There are 9 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.24471C>T	p.Gly8157Gly	synonymous	Exon 84 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.23520C>T	p.Gly7840Gly	synonymous	Exon 82 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.20739C>T	p.Gly6913Gly	synonymous	Exon 81 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.24471C>T	p.Gly8157Gly	synonymous	Exon 84 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.24471C>T	p.Gly8157Gly	synonymous	Exon 84 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.24195C>T	p.Gly8065Gly	synonymous	Exon 82 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00504 AC: 766 AN: 152116 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00115 AC: 287 AN: 248532 AF XY: 0.000927

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.000812

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000522 AC: 763 AN: 1461510 Hom.: 12 Cov.: 36 AF XY: 0.000439 AC XY: 319 AN XY: 727040

African (AFR) AF: 0.0182 AC: 609 AN: 33466

American (AMR) AF: 0.000894 AC: 40 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111740

Other (OTH) AF: 0.00134 AC: 81 AN: 60364

GnomAD4 genome AF: 0.00513 AC: 781 AN: 152234 Hom.: 9 Cov.: 33 AF XY: 0.00536 AC XY: 399 AN XY: 74444

African (AFR) AF: 0.0178 AC: 739 AN: 41552

American (AMR) AF: 0.00164 AC: 25 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67988

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00288 Hom.: 3

Bravo AF: 0.00582

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		0.28
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113391261; hg19: chr2-179583456;