NM_001267550.2:c.24909G>A

Variant names:

• chr2-178718097-C-T
• rs72648983
• NM_001267550.2:c.24909G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.24909G>A​(p.Lys8303Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,106 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (33 hom., cov: 33)
  • Exomes 𝑓: 0.010 (110 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: -0.260
• Publications: 3 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=-0.47).
• BP6: Variant 2-178718097-C-T is Benign according to our data. Variant chr2-178718097-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0183 (2792/152188) while in subpopulation AFR AF = 0.0369 (1532/41542). AF 95% confidence interval is 0.0353. There are 33 homozygotes in GnomAd4. There are 1425 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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.24909G>A	p.Lys8303Lys	synonymous	Exon 86 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.23958G>A	p.Lys7986Lys	synonymous	Exon 84 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.21177G>A	p.Lys7059Lys	synonymous	Exon 83 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.24909G>A	p.Lys8303Lys	synonymous	Exon 86 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.24909G>A	p.Lys8303Lys	synonymous	Exon 86 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.24633G>A	p.Lys8211Lys	synonymous	Exon 84 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2787 AN: 152070 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0208

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00753

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00812

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0130 AC: 3228 AN: 248330 AF XY: 0.0132

Gnomad AFR exome AF: 0.0384

Gnomad AMR exome AF: 0.00948

Gnomad ASJ exome AF: 0.00766

Gnomad EAS exome AF: 0.00640

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.00990

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0101 AC: 14780 AN: 1460918 Hom.: 110 Cov.: 35 AF XY: 0.0104 AC XY: 7524 AN XY: 726776

African (AFR) AF: 0.0376 AC: 1258 AN: 33456

American (AMR) AF: 0.0101 AC: 453 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 211 AN: 26126

East Asian (EAS) AF: 0.00345 AC: 137 AN: 39692

South Asian (SAS) AF: 0.0175 AC: 1512 AN: 86250

European-Finnish (FIN) AF: 0.0168 AC: 886 AN: 52852

Middle Eastern (MID) AF: 0.0186 AC: 107 AN: 5762

European-Non Finnish (NFE) AF: 0.00855 AC: 9510 AN: 1111702

Other (OTH) AF: 0.0117 AC: 706 AN: 60358

GnomAD4 genome AF: 0.0183 AC: 2792 AN: 152188 Hom.: 33 Cov.: 33 AF XY: 0.0192 AC XY: 1425 AN XY: 74400

African (AFR) AF: 0.0369 AC: 1532 AN: 41542

American (AMR) AF: 0.0207 AC: 317 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.00735 AC: 38 AN: 5170

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4812

European-Finnish (FIN) AF: 0.0188 AC: 199 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00812 AC: 552 AN: 67966

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

Alfa AF: 0.0120 Hom.: 14

Bravo AF: 0.0189

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.00905

EpiControl AF: 0.0103

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	not provided (4)
-	-	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	-0.47
CADD	Benign	1.4
DANN	Benign	0.75
PhyloP100		-0.26
Mutation Taster		=88/12	polymorphism

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: rs72648983; hg19: chr2-179582824; COSMIC: COSV59946447; COSMIC: COSV59946447;