2-178684346-C-T

Variant names:

• chr2-178684346-C-T
• rs372124201
• NM_001267550.2:c.32706G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BP6 BP7

The NM_001267550.2(TTN):​c.32706G>A​(p.Ala10902Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,613,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A10902A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.876
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15).
• BP6: Variant 2-178684346-C-T is Benign according to our data. Variant chr2-178684346-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228082.
• BP7: Synonymous conserved (PhyloP=0.876 with no splicing effect.

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.32706G>A	p.Ala10902Ala	synonymous	Exon 132 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.31755G>A	p.Ala10585Ala	synonymous	Exon 130 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.28974G>A	p.Ala9658Ala	synonymous	Exon 129 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.32706G>A	p.Ala10902Ala	synonymous	Exon 132 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.32706G>A	p.Ala10902Ala	synonymous	Exon 132 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.32430G>A	p.Ala10810Ala	synonymous	Exon 130 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 25 AN: 151904 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000925 AC: 23 AN: 248634 AF XY: 0.0000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000798

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000972 AC: 142 AN: 1461256 Hom.: 0 Cov.: 31 AF XY: 0.0000963 AC XY: 70 AN XY: 726890

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.000157 AC: 7 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000954 AC: 106 AN: 1111660

Other (OTH) AF: 0.0000994 AC: 6 AN: 60356

GnomAD4 genome AF: 0.000165 AC: 25 AN: 151904 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74164

African (AFR) AF: 0.0000725 AC: 3 AN: 41356

American (AMR) AF: 0.00118 AC: 18 AN: 15244

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	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	-0.15
CADD	Benign	5.9
DANN	Benign	0.76
PhyloP100		0.88
Mutation Taster		=88/12	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: rs372124201; hg19: chr2-179549073;