rs1446730289

Variant names:

• chr2-178657894-G-A
• rs1446730289
• NM_001267550.2:c.37860C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001267550.2(TTN):​c.37860C>T​(p.Ala12620Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 11)
  • Exomes 𝑓: 0.000033 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.20
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-178657894-G-A is Benign according to our data. Variant chr2-178657894-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 467087.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.2 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.37860C>T	p.Ala12620Ala	synonymous_variant	Exon 187 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.37860C>T	p.Ala12620Ala	synonymous_variant	Exon 187 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000674 AC: 6 AN: 89070 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000912

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000992 AC: 2 AN: 20162 AF XY: 0.0000962

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000769

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000328 AC: 30 AN: 914798 Hom.: 5 Cov.: 12 AF XY: 0.0000284 AC XY: 13 AN XY: 457220

African (AFR) AF: 0.00 AC: 0 AN: 19400

American (AMR) AF: 0.00145 AC: 27 AN: 18574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18368

East Asian (EAS) AF: 0.00 AC: 0 AN: 33300

South Asian (SAS) AF: 0.00 AC: 0 AN: 52274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2902

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 698740

Other (OTH) AF: 0.0000731 AC: 3 AN: 41012

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000674 AC: 6 AN: 89070 Hom.: 0 Cov.: 11 AF XY: 0.0000726 AC XY: 3 AN XY: 41306

African (AFR) AF: 0.00 AC: 0 AN: 21500

American (AMR) AF: 0.000912 AC: 6 AN: 6578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2430

East Asian (EAS) AF: 0.00 AC: 0 AN: 3388

South Asian (SAS) AF: 0.00 AC: 0 AN: 2090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 45836

Other (OTH) AF: 0.00 AC: 0 AN: 1132

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.33
DANN	Benign	0.62
PhyloP100		-1.2
Mutation Taster		=100/0	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: rs1446730289; hg19: chr2-179522621;