rs1481421931

Variant names:

• chr2-178654836-G-T
• rs1481421931
• NM_001267550.2:c.38123-8C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):​c.38123-8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 8)
  • Exomes 𝑓: 0.000024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 splice_region, intron
• Scores: Splicing: ADA: 0.9005
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.38123-8C>A		splice_region_variant, intron_variant	Intron 190 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.38123-8C>A		splice_region_variant, intron_variant	Intron 190 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000613 AC: 4 AN: 65296 Hom.: 0 Cov.: 8

Gnomad AFR AF: 0.0000857

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: 0.0000789

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000241 AC: 12 AN: 497820 Hom.: 0 Cov.: 6 AF XY: 0.0000346 AC XY: 9 AN XY: 260206

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11946

American (AMR) AF: 0.00 AC: 0 AN: 17268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13730

East Asian (EAS) AF: 0.00 AC: 0 AN: 29056

South Asian (SAS) AF: 0.00 AC: 0 AN: 42578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2008

European-Non Finnish (NFE) AF: 0.0000314 AC: 10 AN: 318142

Other (OTH) AF: 0.0000744 AC: 2 AN: 26872

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000243844), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000613 AC: 4 AN: 65296 Hom.: 0 Cov.: 8 AF XY: 0.0000677 AC XY: 2 AN XY: 29522

African (AFR) AF: 0.0000857 AC: 1 AN: 11666

American (AMR) AF: 0.00 AC: 0 AN: 4716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1932

East Asian (EAS) AF: 0.00 AC: 0 AN: 2048

South Asian (SAS) AF: 0.00 AC: 0 AN: 1190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000789 AC: 3 AN: 38020

Other (OTH) AF: 0.00 AC: 0 AN: 790

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.86
PhyloP100		3.2
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.27
SpliceAI score (max)		0.010		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: rs1481421931; hg19: chr2-179519563;