2-178774570-C-T

Variant names:

• chr2-178774570-C-T
• rs3816781
• NM_001267550.2:c.6791-97G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.6791-97G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,162,060 control chromosomes in the GnomAD database, including 549,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66197 hom., cov: 32)
  • Exomes 𝑓: 0.98 (482920 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.466

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-178774570-C-T is Benign according to our data. Variant chr2-178774570-C-T is described in ClinVar as [Benign]. Clinvar id is 1275365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.6791-97G>A		intron_variant	Intron 29 of 362	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.6791-97G>A		intron_variant	Intron 29 of 45	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.6791-97G>A		intron_variant	Intron 29 of 362	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.6791-97G>A		intron_variant	Intron 29 of 45	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes AF: 0.929 AC: 141325 AN: 152130 Hom.: 66170 Cov.: 32

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.958

Gnomad ASJ AF: 0.994

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.980

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.936

GnomAD4 exome AF: 0.977 AC: 986749 AN: 1009812 Hom.: 482920 Cov.: 13 AF XY: 0.978 AC XY: 504185 AN XY: 515790

Gnomad4 AFR exome AF: 0.794

Gnomad4 AMR exome AF: 0.943

Gnomad4 ASJ exome AF: 0.993

Gnomad4 EAS exome AF: 0.869

Gnomad4 SAS exome AF: 0.958

Gnomad4 FIN exome AF: 0.977

Gnomad4 NFE exome AF: 0.992

Gnomad4 OTH exome AF: 0.966

GnomAD4 genome AF: 0.929 AC: 141402 AN: 152248 Hom.: 66197 Cov.: 32 AF XY: 0.930 AC XY: 69189 AN XY: 74436

Gnomad4 AFR AF: 0.802

Gnomad4 AMR AF: 0.958

Gnomad4 ASJ AF: 0.994

Gnomad4 EAS AF: 0.874

Gnomad4 SAS AF: 0.951

Gnomad4 FIN AF: 0.980

Gnomad4 NFE AF: 0.991

Gnomad4 OTH AF: 0.937

Alfa AF: 0.978 Hom.: 67636

Bravo AF: 0.918

Asia WGS AF: 0.903 AC: 3137 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.42
DANN	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs3816781; hg19: chr2-179639297;