rs369959066

Variant names:

• chr2-178633295-G-A
• rs369959066
• NM_001267550.2:c.42978C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178633295-G-A
• chr2-178633295-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001267550.2(TTN):​c.42978C>T​(p.Tyr14326Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,613,060 control chromosomes in the GnomAD database, including 8 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 0.00026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (7 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:12
• Conservation: PhyloP100: 0.838
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-178633295-G-A is Benign according to our data. Variant chr2-178633295-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178218.
• BP7: Synonymous conserved (PhyloP=0.838 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000256 (39/152114) while in subpopulation SAS AF = 0.0056 (27/4824). AF 95% confidence interval is 0.00395. There are 1 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.42978C>T	p.Tyr14326Tyr	synonymous	Exon 233 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.38055C>T	p.Tyr12685Tyr	synonymous	Exon 183 of 313	NP_001243779.1
	TTN	NM_133378.4		c.35274C>T	p.Tyr11758Tyr	synonymous	Exon 182 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.42978C>T	p.Tyr14326Tyr	synonymous	Exon 233 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.42822C>T	p.Tyr14274Tyr	synonymous	Exon 231 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.42702C>T	p.Tyr14234Tyr	synonymous	Exon 231 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000866 AC: 215 AN: 248280 AF XY: 0.00114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000187

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000474 AC: 692 AN: 1460946 Hom.: 7 Cov.: 32 AF XY: 0.000669 AC XY: 486 AN XY: 726704

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.000112 AC: 5 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39646

South Asian (SAS) AF: 0.00629 AC: 542 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00400 AC: 23 AN: 5756

European-Non Finnish (NFE) AF: 0.0000729 AC: 81 AN: 1111466

Other (OTH) AF: 0.000646 AC: 39 AN: 60336

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152114 Hom.: 1 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74342

African (AFR) AF: 0.0000722 AC: 3 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67946

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000147

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	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	-0.53
CADD	Benign	1.9
DANN	Benign	0.77
PhyloP100		0.84
Mutation Taster		=87/13	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: rs369959066; hg19: chr2-179498022; COSMIC: COSV60227120; COSMIC: COSV60227120;