rs34591340

Positions:

chr4-113345966-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001148.6(ANK2):c.4315G>T(p.Gly1439Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3O:1

Conservation

PhyloP100: 2.89

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 Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18178931).

BP6

Variant 4-113345966-G-T is Benign according to our data. Variant chr4-113345966-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67606.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2, not_provided=1, Benign=1}. Variant chr4-113345966-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000223 (34/152300) while in subpopulation NFE AF= 0.000397 (27/68024). AF 95% confidence interval is 0.00028. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001148.6 link	c.4315G>T	p.Gly1439Cys	missense_variant	35/46	ENST00000357077.9	NP_001139.3	Q01484-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9 link	c.4315G>T	p.Gly1439Cys	missense_variant	35/46	1	NM_001148.6	ENSP00000349588.4		Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000283

AC:

AN:

251232

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000502

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000332

AC:

485

AN:

1461436

Hom.:

Cov.:

AF XY:

0.000330

AC XY:

240

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000399

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000223

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000367

Hom.:

Bravo

AF:

0.000234

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiac arrhythmia, ankyrin-B-related

Uncertain:3Benign:1

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 35 p.Gly1439Cys (c.4315G>T): This variant has been reported in the literature in at least 1 individual with HCM (Lopes 2015 PMID:25351510) as well as at least 2 individuals with a clinical suspicion of Long QT syndrome (Lieve 2013 PMID:23631430, Mullally 2013 PMID:23174487). This variant is present in 64/126500 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs34591340). This variant is present in ClinVar (Variation ID:67606). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies involving cardiomyocytes suggest that this variant may not impact the protein and displays properties similar to wild-type (Mohler 2007 PMID:17242276). Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (OMIM, PMID:12571597, PMID:15178757, PMID:17242276.) (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance. Limited evidence (PMID:26230511). (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to cysteine (exon 35). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition: 0.0002795 (79 het, 0 hom). (P) 0309 An alternative amino acid change at the same position has been observed in gnomAD p.(Gly1439Asp): 0.000004 (1 het, 0 hom). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. Major change. High conservation. (N) 0600 - Variant is located in an annotated domain or motif. UPA domain (NCBI_Conserved Domains, (N) 0704 - Comparable variant has low previous evidence for pathogenicity. NM_ 001148.4(ANK2):c.4315G>A; Gly1439Ser: considered Likely pathogenic in 1 patient with atrial fibrillation (PMID: 30276209). (P) 0808 - Previous reports of pathogenicity are conflicting. ClinVar: 5x VUS, 2x Likely benign, 1x benign, 1 not provided, with most recent submissions and evaluations tending towards benign/ likely benign. LOVD3: Likely benign x1 (VKGL Data sharing initiative, Netherlands). Earlier publications indicate an association with LQTS (PMID: 23174487, PMID: 28988457). However, more recent reports suggest is a VUS, with not enough evidence, or a VUS, likely benign (PMID: 28589536, PMID: 31638414, respectively. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1004 - Moderate functional evidence supporting normal protein function. PMID:17242276: Referred to as G4216T, G1406C, due to a different transcript used. Effects were similar to wildtype, and rescued abnormal phenotype (contraction rate and spatial patterns of Ca2+ release in ankyrin-B heterozygous and homozygous knockout mice. (B) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided

Uncertain:2Other:1

not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:17242276). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2024	Reported in association with LQTS, HCM, and early onset atrial fibrillation; no case-specific clinical or segregation data were provided in these publications (PMID: 23174487, 25351510, 31638414); Identified in one individual of Mexican American ancestry from a control cohort of 190 anonymized individuals; variant reported as p.(G1406C) due to alternate nomenclature (PMID: 17242276); Functional studies in mouse neonatal cardiomyocytes suggest this variant may not impact ankyrin-B function; the clinical validity of these studies remains to be established (PMID: 17242276); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23631430, 25351510, 28988457, 22581653, 31638414, 17242276, 23174487) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 21, 2017	p.Gly1439Cys (c.4315G>T), was identified in exon 35 ANK2 (NM_001148.4) Given the weak case data and its prevalence in the general population, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 2 unrelated cases of Long QT syndrome (not including this patient's family). The case data is weak. This variant is present in ClinVar. It is interpreted as likely benign by GeneDx and Ambry genetics. It is interpreted as a variant of uncertain significance by Illumina Clinical Services. It has also been submitted by Royal Brompton, but they did not provide a classification. This variant was seen in 1 out of 855 unrelated patients referred for Long QT testing (Vieve et al 2013). The researchers classified it as a VUS/likely benign. Clinical information on this individual, including their QTc interval, is available for review. It is important to note that this patient is likely the same as a patient present in ClinVar, submitted by GeneDx. It was also present in 1 out of 403 individuals with Long QT syndrome (Mullally et al 2013). The glycine at codon 1439 is moderately conserved across species, as are neighboring amino acids. Nearby codons have been classified as likely benign or there are conflicting interpretations of pathogenicity. The variant was reported online in 71 of 122,869 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 57 of 55,746 individuals of European descent (MAF=0.017%), 6 of 16,779 individuals of Latino descent, 4 of 11,150 individuals of Finnish descent, 2 of 7,651 individuals of African descent and 2 of 2,738 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

Long QT syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	- -

Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 18, 2019

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2024

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

Pathogenic

0.67

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;.;T;.;D;T;T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

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

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.18

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

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.4

.;.;.;L;L;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.0

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

REVEL

Benign

0.27

Sift

Uncertain

0.025

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

Sift4G

Uncertain

0.035

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

Polyphen

0.035, 0.14, 0.017

.;B;.;B;.;.;B;.

Vest4

0.69, 0.63, 0.91, 0.93, 0.57, 0.41

MVP

0.86

MPC

1.4

ClinPred

0.17

GERP RS

6.1

Varity_R

0.71

gMVP

0.42

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