4-113049603-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000506722.5(ANK2):c.22-124813C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,506,396 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0082 (10 hom., cov: 32)
  • Exomes 𝑓: 0.012 (150 hom.)
• Consequence: ANK2 ENST00000506722.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.00

Genes affected

ANK2 (HGNC:493): (ankyrin 2) This gene encodes a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. The protein encoded by this gene is required for targeting and stability of Na/Ca exchanger 1 in cardiomyocytes. Mutations in this gene cause long QT syndrome 4 and cardiac arrhythmia syndrome. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Dec 2011]

ANK2-AS1 (HGNC:40076): (ANK2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 4-113049603-C-T is Benign according to our data. Variant chr4-113049603-C-T is described in ClinVar as [Benign]. Clinvar id is 1253934.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00817 (1244/152248) while in subpopulation SAS AF= 0.017 (82/4824). AF 95% confidence interval is 0.014. There are 10 homozygotes in gnomad4. There are 595 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6			upstream_gene_variant		ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2-AS1	ENST00000508959.1	n.126-14809G>A		intron_variant, non_coding_transcript_variant		2
ANK2	ENST00000357077.9			upstream_gene_variant		1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.00818 AC: 1244 AN: 152130 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.0125 AC: 16873 AN: 1354148 Hom.: 150 Cov.: 29 AF XY: 0.0127 AC XY: 8477 AN XY: 666896

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00334

Gnomad4 ASJ exome AF: 0.00553

Gnomad4 EAS exome AF: 0.0000294

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.00880

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.00910

GnomAD4 genome AF: 0.00817 AC: 1244 AN: 152248 Hom.: 10 Cov.: 32 AF XY: 0.00799 AC XY: 595 AN XY: 74446

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0101 Hom.: 2

Bravo AF: 0.00727

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	17
Dann	Benign	0.87

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs80077887; hg19: chr4-113970759;