rs371140114

Variant names:

• chr2-178569323-A-G
• rs371140114
• NM_001267550.2:c.76809T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_001267550.2(TTN):​c.76809T>C​(p.Ser25603Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000248 in 1,613,134 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.48
• 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: Benign. The variant received -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-178569323-A-G is Benign according to our data. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569323-A-G is described in CliVar as Likely_benign. Clinvar id is 535151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.76809T>C	p.Ser25603Ser	synonymous_variant	Exon 326 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.76809T>C	p.Ser25603Ser	synonymous_variant	Exon 326 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461020 Hom.: 0 Cov.: 41 AF XY: 0.00000138 AC XY: 1 AN XY: 726780

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111486

Other (OTH) AF: 0.0000331 AC: 2 AN: 60344

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15254

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 16, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.39
DANN	Benign	0.79
PhyloP100		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=48/52	disease causing

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: rs371140114; hg19: chr2-179434050;