NM_001267550.2:c.57263-6T>C

Variant names:

• chr2-178597825-A-G
• rs562237741
• NM_001267550.2:c.57263-6T>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.57263-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,848 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001939
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.902
• 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=-0.75).
• BP6: Variant 2-178597825-A-G is Benign according to our data. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-178597825-A-G is described in CliVar as Likely_benign. Clinvar id is 1087499.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.57263-6T>C		splice_region_variant, intron_variant	Intron 293 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.57263-6T>C		splice_region_variant, intron_variant	Intron 293 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00000404 AC: 1 AN: 247444 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

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: 0.00000411 AC: 6 AN: 1460594 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726548

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111474

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74432

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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

Dec 02, 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	-0.75
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		0.90
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.040		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: rs562237741; hg19: chr2-179462552;