2-178546904-A-G

Variant names:

• chr2-178546904-A-G
• rs727505200
• NM_001267550.2:c.94524T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001267550.2(TTN):​c.94524T>C​(p.Asp31508Asp) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000035 in 1,427,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TTN NM_001267550.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.00007730
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 4.56
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-178546904-A-G is Benign according to our data. Variant chr2-178546904-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179892.

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.94524T>C	p.Asp31508Asp	splice_region synonymous	Exon 341 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.89601T>C	p.Asp29867Asp	splice_region synonymous	Exon 291 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.86820T>C	p.Asp28940Asp	splice_region synonymous	Exon 290 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.94524T>C	p.Asp31508Asp	splice_region synonymous	Exon 341 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.94368T>C	p.Asp31456Asp	splice_region synonymous	Exon 339 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.94248T>C	p.Asp31416Asp	splice_region synonymous	Exon 339 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000224 AC: 5 AN: 223622 AF XY: 0.0000250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1427082 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 705202

African (AFR) AF: 0.00 AC: 0 AN: 32520

American (AMR) AF: 0.00 AC: 0 AN: 41842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23910

East Asian (EAS) AF: 0.00 AC: 0 AN: 39252

South Asian (SAS) AF: 0.0000496 AC: 4 AN: 80600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092650

Other (OTH) AF: 0.00 AC: 0 AN: 58726

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.028
DANN	Benign	0.86
PhyloP100		4.6
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000077
dbscSNV1_RF	Benign	0.052
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: rs727505200; hg19: chr2-179411631;