rs45570339

chr4-113363442-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001148.6(ANK2):c.10861C>G(p.Leu3621Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,613,430 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L3621L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9 O:1
• Conservation: PhyloP100: 0.717

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK2
• BP4: Computational evidence support a benign effect (MetaRNN=0.009227902).
• BP6: Variant 4-113363442-C-G is Benign according to our data. Variant chr4-113363442-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67597.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, not_provided=1, Likely_benign=2, Uncertain_significance=1}. Variant chr4-113363442-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.003 (457/152216) while in subpopulation AFR AF= 0.0106 (440/41530). AF 95% confidence interval is 0.00978. There are 0 homozygotes in gnomad4. There are 233 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 457 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.10861C>G	p.Leu3621Val	missense_variant	40/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.10861C>G	p.Leu3621Val	missense_variant	40/46	1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 457 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000669 AC: 168 AN: 251060 Hom.: 1 AF XY: 0.000516 AC XY: 70 AN XY: 135664

Gnomad AFR exome AF: 0.00923

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000288 AC: 421 AN: 1461214 Hom.: 3 Cov.: 31 AF XY: 0.000230 AC XY: 167 AN XY: 726914

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74408

Gnomad4 AFR AF: 0.0106

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000804 Hom.: 0

Bravo AF: 0.00324

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000857 AC: 104

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 27, 2019	The ANK2 c.10861C>G, p.Leu3621Val variant (rs45570339) is reported in the literature in one individual affected with long QT syndrome (Sherman 2005). This variant is found in the African population with an allele frequency of 0.9% (239/24,958 alleles, including 1 homozygote) in the Genome Aggregation Database. The leucine at codon 3621 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2:probably damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Leu3621Val variant is uncertain at this time. References: Sherman et al. Targeted mutational analysis of ankyrin-B in 541 consecutive, unrelated patients referred for long QT syndrome genetic testing and 200 healthy subjects. Heart Rhythm. 2005 Nov;2(11):1218-23. Gene statement: Pathogenic variants in ANK2 are associated with autosomal dominant ankyrin-B-related cardiac arrhythmia and long QT syndrome 4 (MIM: 600919). -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 20, 2018	Variant summary: ANK2 c.10861C>G (p.Leu3621Val) results in a conservative amino acid change located in the Death domain of the encoded protein sequence (InterPro). Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00091 in 276772 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0097 in the gnomAD database, including 1 homozygote. The observed variant frequency within African control individuals in the gnomAD database is approximately 970 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2018	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. -

Long QT syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cardiac arrhythmia, ankyrin-B-related Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16253912). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	22
Dann	Benign	0.86
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.81	T;T;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.0092	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.049	D
MutationTaster	Benign	0.99	D;D;D;D;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.48	N;N;N;N;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	1.0	T;T;T;T;T;T;T
Sift4G	Benign	0.80	T;T;T;T;T;T;T
Polyphen		0.0090	B;B;.;.;B;.;.
Vest4		0.27
MVP		0.95
MPC		0.44
ClinPred		0.0087	T
GERP RS		4.5
Varity_R		0.043
gMVP		0.31

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: rs45570339; hg19: chr4-114284598; COSMIC: COSV100005116; COSMIC: COSV100005116;