chr4-113354846-G-T

Position:

chr4-113354846-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_001148.6(ANK2):c.6228G>T(p.Lys2076Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,614,002 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: 0.555

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:

ANK2 (HGNC:):

ANK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 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=0.055000365).

BP6

Variant 4-113354846-G-T is Benign according to our data. Variant chr4-113354846-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191538.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=5}.

BS2

High AC in GnomAd4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001148.6 linkuse as main transcript	c.6228G>T	p.Lys2076Asn	missense_variant	38/46	ENST00000357077.9	NP_001139.3	Q01484-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9 linkuse as main transcript	c.6228G>T	p.Lys2076Asn	missense_variant	38/46	1	NM_001148.6	ENSP00000349588.4		Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000335

AC:

AN:

250964

Hom.:

AF XY:

0.000332

AC XY:

AN XY:

135616

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.000635

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000394

AC:

576

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000432

AC XY:

314

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000374

Gnomad4 NFE exome

AF:

0.000479

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000453

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000636

Hom.:

Bravo

AF:

0.000348

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000371

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ANK2: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 02, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2024	Reported in one family with primary electrical disease, in an infant deceased from SIDS, and in an individual with Emery-Dreifuss muscular dystrophy (PMID: 28341588, 28074886, 31862442); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28074886, 31862442, 28341588, 18790697, 26109584, 1830053) -

Long QT syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Congenital long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Dec 01, 2023

Heterozygous variant NM_001148:c.6228G>T (p.Lys2076Asn) in the ANK2 gene was found on WES data in female proband (13 y.o., Caucasian) with Long QT syndrome. Additional rare candidate variant NM_000891:c.1222C>G (p.Leu408Val) (Class III of pathogenicity) in the KCNJ2 gene was found in this proband. The NM_001148:c.6228G>T variant is in The Genome Aggregation Database (gnomAD) v2.1.1 and v4.0.0 with total MAF 0.0004108 and 0.0003996 respectively (Date of access 01-12-2023). Clinvar contains an entry for this variant (Variation ID: 191538). This variant has been reported in 3 studies in patients with variable phenotypes (PMID: 28074886, 28341588, 31862442). Most in silico predictors show benign result of the protein change (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: BP4. -

Cardiac arrhythmia, ankyrin-B-related

Uncertain:1

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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Oct 17, 2022

Variant summary: ANK2 c.6228G>T (p.Lys2076Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 250964 control chromosomes, predominantly at a frequency of 0.00064 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 64-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 Non-Finnish European origin. c.6228G>T has been reported in the literature in individuals affected with Primary electrical disease, Sudden infant death syndrome and Emery-Dreifuss muscular dystrophy (Neubauer_2017, Proost_2017, Meinke_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2018

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

0.29

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.055

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.9

L;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.51

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.027

D;D

Sift4G

Benign

0.32

T;T

Vest4

0.085

MVP

0.45

MPC

0.19

ClinPred

0.039

GERP RS

4.6

Varity_R

0.078

gMVP

0.021

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