rs370434818

Variant names:

• chr2-178768164-T-A
• rs370434818
• NM_001267550.2:c.9164-9A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178768164-T-A
• chr2-178768164-T-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001267550.2(TTN):​c.9164-9A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,818 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: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TTN NM_001267550.2 intron
• Scores: Splicing: ADA: 0.00003067
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.52
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-178768164-T-A is Benign according to our data. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178768164-T-A is described in CliVar as Likely_benign. Clinvar id is 2937988.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.9164-9A>T		intron_variant	Intron 38 of 362	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.9164-9A>T		intron_variant	Intron 38 of 45	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.9164-9A>T		intron_variant	Intron 38 of 362	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.9164-9A>T		intron_variant	Intron 38 of 45	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

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: 0.00000753 AC: 11 AN: 1461604 Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 6 AN XY: 727112

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111880

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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

Jul 19, 2023

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	-0.71
CADD	Benign	0.28
DANN	Benign	0.68
PhyloP100		-1.5
PromoterAI		-0.00060	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0
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: rs370434818; hg19: chr2-179632891;