rs35728190

chr4-113363489-C-T

Variant summary

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

The NM_001148.6(ANK2):c.10888+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,612,242 control chromosomes in the GnomAD database, including 9,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (923 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8362 hom.)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.838

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=-0.91).
• BP6: Variant 4-113363489-C-T is Benign according to our data. Variant chr4-113363489-C-T is described in ClinVar as [Benign]. Clinvar id is 136394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113363489-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.10888+20C>T		intron_variant		ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.10888+20C>T		intron_variant		1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16000 AN: 152056 Hom.: 923 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0874

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0996

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.0896 AC: 22487 AN: 251068 Hom.: 1241 AF XY: 0.0901 AC XY: 12223 AN XY: 135692

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.0613

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0352

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.103 AC: 150601 AN: 1460068 Hom.: 8362 Cov.: 32 AF XY: 0.102 AC XY: 74297 AN XY: 726374

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.0641

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.0356

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.105 AC: 16008 AN: 152174 Hom.: 923 Cov.: 32 AF XY: 0.103 AC XY: 7637 AN XY: 74406

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.0872

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0996

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.121

Alfa AF: 0.119 Hom.: 194

Bravo AF: 0.106

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiac arrhythmia, ankyrin-B-related Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.099
Dann	Benign	0.20

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: rs35728190; hg19: chr4-114284645;