4-113367764-C-A

Position:

chr4-113367764-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_001148.6(ANK2):c.11231C>A(p.Thr3744Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 0 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:8O:1

Conservation

PhyloP100: 0.779

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANK2. . Gene score misZ 1.9641 (greater than the threshold 3.09). Trascript score misZ 4.2513 (greater than threshold 3.09). GenCC has associacion of gene with heart conduction disease, Brugada syndrome, long QT syndrome, complex neurodevelopmental disorder, cardiac arrhythmia, ankyrin-B-related, catecholaminergic polymorphic ventricular tachycardia.

BP4

Computational evidence support a benign effect (MetaRNN=0.17442057).

BP6

Variant 4-113367764-C-A is Benign according to our data. Variant chr4-113367764-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 18057.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, not_provided=1, Benign=1, Uncertain_significance=4}. Variant chr4-113367764-C-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001148.6 linkuse as main transcript	c.11231C>A	p.Thr3744Asn	missense_variant	42/46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9 linkuse as main transcript	c.11231C>A	p.Thr3744Asn	missense_variant	42/46	1	NM_001148.6	ENSP00000349588	A2	Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000625

AC:

157

AN:

251200

Hom.:

AF XY:

0.000626

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00122

AC:

1778

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

840

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00156

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152112

Hom.:

Cov.:

AF XY:

0.000687

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.000695

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000618

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ANK2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	This variant is associated with the following publications: (PMID: 16253912, 23631430, 15178757, 31539150, 32164423, 23861362) -

Cardiac arrhythmia, ankyrin-B-related

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ANK2 NM_001148.4 exon 42 p.Thr3744Asn (c.11231C>A): This variant has been reported in the literature in at least 4 individuals with clinical suspicion of arrhythmia (Mohler 2004 PMID:15178757, Lieve 2013 PMID:23631430). However, this variant is present in 0.1% (157/126452) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912705). This variant is present in ClinVar, with conflicting classifications of this variant (Variation ID:18057). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2004	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 12, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We classify this variant as a variant of unknown significance. This variant has been previously reported in two unrelated individuals with borderline prolonged QT intervals (Mohler P et at., 2004; due to alternative nomenclature, they report it as Thr1626Asn). One of the reported individuals had a daughter, also heterozygous for the variant, who died suddenly at age 19 with no prior cardiac symptoms. All other carriers of the variant in the two families were asymptomatic. This is a conservative amino acid change, resulting in the replacement of a threonine (polar) with an asparagine (polar). Threonine at this location is conserved across most mammalian species for which data is available with the exception of the mouse and x-tropicalis. In silico analysis with PolyPhen-2 predicts the variant to be “possibly damaging” with a score of 0.951. In total, the variant has been seen in at least 12/6700 individuals from published controls and publicly available population datasets. This variant is listed in the NHLBI Exome Sequencing Project dataset, where it was found in 11 of 6503 genotyped individuals (2 of 2203 African Americans and 9 of 4300 European Americans), indicating that it may be a rare benign variant. Another variant affecting the same residue, T3744P, was also seen in 1 of 6503 genotyped individuals. This variant, T3744N, has been listed in dpSNP, but has not been documented in 1000 genomes. It was observed in 1 of 200 published control individuals of African American descent (Sherman J et al., 2005). -

Long QT syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 25, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	- -

Cardiac arrhythmia

Benign:1Other:1

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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 Cardiac arrhythmia in the following publications (PMID:15178757). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.33

.;.;T;T;T;.;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.17

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

2.0

.;.;M;.;.;.;.

MutationTaster

Benign

2.7e-10

A;A;A;A;A;A

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.82

N;N;N;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.030

D;D;D;D;D;D;D

Sift4G

Benign

0.56

T;T;T;T;T;T;D

Polyphen

0.55

P;P;.;.;B;.;.

Vest4

0.20

MVP

0.65

MPC

0.21

ClinPred

0.019

GERP RS

3.0

Varity_R

0.052

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over