rs72556367

chr4-113339332-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001148.6(ANK2):c.3893+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,609,396 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (25 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (29 hom.)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0300

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-113339332-T-C is Benign according to our data. Variant chr4-113339332-T-C is described in ClinVar as [Benign]. Clinvar id is 238579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113339332-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00959 (1462/152376) while in subpopulation AFR AF= 0.0332 (1379/41586). AF 95% confidence interval is 0.0317. There are 25 homozygotes in gnomad4. There are 693 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1456 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.3893+10T>C		intron_variant		ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.3893+10T>C		intron_variant		1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.00956 AC: 1456 AN: 152258 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00248 AC: 622 AN: 251306 Hom.: 11 AF XY: 0.00186 AC XY: 252 AN XY: 135842

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000946 AC: 1378 AN: 1457020 Hom.: 29 Cov.: 29 AF XY: 0.000855 AC XY: 620 AN XY: 725204

Gnomad4 AFR exome AF: 0.0336

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000406

Gnomad4 OTH exome AF: 0.00211

GnomAD4 genome AF: 0.00959 AC: 1462 AN: 152376 Hom.: 25 Cov.: 32 AF XY: 0.00930 AC XY: 693 AN XY: 74518

Gnomad4 AFR AF: 0.0332

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00698 Hom.: 3

Bravo AF: 0.0112

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -

Cardiac arrhythmia, ankyrin-B-related Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.96
Dann	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs72556367; hg19: chr4-114260488;