2-178612963-A-G

Variant names:

• chr2-178612963-A-G
• rs72677247
• NM_001267550.2:c.49758T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.49758T>C​(p.Tyr16586Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,612,730 control chromosomes in the GnomAD database, including 4 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 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (4 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9
• Conservation: PhyloP100: -0.233
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-178612963-A-G is Benign according to our data. Variant chr2-178612963-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228104.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000178 (260/1460654) while in subpopulation SAS AF = 0.00217 (187/86228). AF 95% confidence interval is 0.00191. There are 4 homozygotes in GnomAdExome4. There are 191 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.49758T>C	p.Tyr16586Tyr	synonymous	Exon 265 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.44835T>C	p.Tyr14945Tyr	synonymous	Exon 215 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.42054T>C	p.Tyr14018Tyr	synonymous	Exon 214 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.49758T>C	p.Tyr16586Tyr	synonymous	Exon 265 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.49602T>C	p.Tyr16534Tyr	synonymous	Exon 263 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.49482T>C	p.Tyr16494Tyr	synonymous	Exon 263 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000379 AC: 94 AN: 248082 AF XY: 0.000557

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000178 AC: 260 AN: 1460654 Hom.: 4 Cov.: 33 AF XY: 0.000263 AC XY: 191 AN XY: 726642

African (AFR) AF: 0.0000299 AC: 1 AN: 33414

American (AMR) AF: 0.0000896 AC: 4 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.00217 AC: 187 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5756

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111338

Other (OTH) AF: 0.000199 AC: 12 AN: 60300

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41538

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67924

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

Alfa AF: 0.0000950 Hom.: 0

Bravo AF: 0.000102

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	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	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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.076
DANN	Benign	0.61
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72677247; hg19: chr2-179477690;