rs141191319

Variant names:

• chr4-113355750-G-A
• rs141191319
• NM_001148.6:c.7132G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-113355750-G-A
• chr4-113355750-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001148.6(ANK2):​c.7132G>A​(p.Glu2378Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,614,086 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2378Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (13 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 2.81
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• cardiac arrhythmia, ankyrin-B-related

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005632758).
• BP6: Variant 4-113355750-G-A is Benign according to our data. Variant chr4-113355750-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188143.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00213 (325/152284) while in subpopulation NFE AF = 0.00341 (232/68002). AF 95% confidence interval is 0.00305. There are 1 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 325 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.7132G>A	p.Glu2378Lys	missense_variant	Exon 38 of 46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.7132G>A	p.Glu2378Lys	missense_variant	Exon 38 of 46	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 326 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00343

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00230 AC: 577 AN: 250666 AF XY: 0.00230

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.00394

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00302 AC: 4408 AN: 1461802 Hom.: 13 Cov.: 35 AF XY: 0.00292 AC XY: 2123 AN XY: 727214

African (AFR) AF: 0.000388 AC: 13 AN: 33468

American (AMR) AF: 0.000581 AC: 26 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 50 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000858 AC: 74 AN: 86258

European-Finnish (FIN) AF: 0.00191 AC: 102 AN: 53410

Middle Eastern (MID) AF: 0.00884 AC: 51 AN: 5766

European-Non Finnish (NFE) AF: 0.00357 AC: 3970 AN: 1111968

Other (OTH) AF: 0.00202 AC: 122 AN: 60394

GnomAD4 genome AF: 0.00213 AC: 325 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74472

African (AFR) AF: 0.000674 AC: 28 AN: 41572

American (AMR) AF: 0.000654 AC: 10 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00313 Hom.: 0

Bravo AF: 0.00196

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00261 AC: 317

EpiCase AF: 0.00234

EpiControl AF: 0.00332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Nov 10, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26230511, 23861362, 23396983, 28465117) -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ANK2: BP4, BS1 -

not specified Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 06, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ANK2 c.7132G>A (p.Glu2378Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 250666 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 230-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 benign. To our knowledge, no occurrence of c.7132G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (2x), likely benign (2x) or VUS. Based on the evidence outlined above, the variant was classified as benign. -

Cardiac arrhythmia, ankyrin-B-related Uncertain:1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome Benign:1

Feb 27, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Apr 24, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		2.8
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.99	N;N
REVEL	Benign	0.050
Sift	Benign	0.058	T;T
Sift4G	Benign	0.22	T;T
Vest4		0.15
MVP		0.49
MPC		0.088
ClinPred		0.0047	T
GERP RS		3.7
Varity_R		0.10
gMVP		0.062
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs141191319; hg19: chr4-114276906; COSMIC: COSV52157571; COSMIC: COSV52157571;