chr2-178525940-A-G

Position:

• chr2-178525940-A-G

Variant summary

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

The NR_038272.1(TTN-AS1):​n.219+2304A>G variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 152,470 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (70 hom., cov: 33)
  • Exomes 𝑓: 0.035 (0 hom.)
• Consequence: TTN-AS1 NR_038272.1 intron, non_coding_transcript
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.168

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 2-178525940-A-G is Benign according to our data. Variant chr2-178525940-A-G is described in ClinVar as [Benign]. Clinvar id is 1262402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN-AS1	NR_038272.1	n.219+2304A>G		intron_variant, non_coding_transcript_variant
TTN	NM_001267550.2			downstream_gene_variant		ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN-AS1	ENST00000659121.1	n.416+2304A>G		intron_variant, non_coding_transcript_variant
TTN	ENST00000589042.5			downstream_gene_variant		5	NM_001267550.2	P1

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3570 AN: 152152 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.00485

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0237

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.0639

Gnomad SAS AF: 0.0323

Gnomad FIN AF: 0.0617

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0215

GnomAD4 exome AF: 0.0350 AC: 7 AN: 200 Hom.: 0 Cov.: 0 AF XY: 0.0234 AC XY: 3 AN XY: 128

Gnomad4 FIN exome AF: 0.0372

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0235 AC: 3572 AN: 152270 Hom.: 70 Cov.: 33 AF XY: 0.0251 AC XY: 1868 AN XY: 74454

Gnomad4 AFR AF: 0.00484

Gnomad4 AMR AF: 0.0237

Gnomad4 ASJ AF: 0.0204

Gnomad4 EAS AF: 0.0642

Gnomad4 SAS AF: 0.0326

Gnomad4 FIN AF: 0.0617

Gnomad4 NFE AF: 0.0253

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0217 Hom.: 4

Bravo AF: 0.0201

Asia WGS AF: 0.0430 AC: 150 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.5
DANN	Benign	0.33

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72629800; hg19: chr2-179390667;