rs35338364

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001148.6(ANK2):c.7831T>C(p.Tyr2611His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000866 in 1,614,072 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2611C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0048 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 7 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.29

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 -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, ANK2

BP4

Computational evidence support a benign effect (MetaRNN=0.00358361).

BP6

Variant 4-113356449-T-C is Benign according to our data. Variant chr4-113356449-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 238590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-113356449-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00483 (736/152250) while in subpopulation AFR AF= 0.017 (707/41542). AF 95% confidence interval is 0.016. There are 6 homozygotes in gnomad4. There are 346 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 731 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6 linkuse as main transcript	c.7831T>C	p.Tyr2611His	missense_variant	38/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9 linkuse as main transcript	c.7831T>C	p.Tyr2611His	missense_variant	38/46	1	NM_001148.6	A2	Q01484-4

Frequencies

GnomAD3 genomes

AF:

0.00481

AC:

731

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

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:

0.00287

GnomAD3 exomes

AF:

0.00128

AC:

320

AN:

250466

Hom.:

AF XY:

0.000835

AC XY:

113

AN XY:

135340

show subpopulations

Gnomad AFR exome

AF:

0.0184

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000453

AC:

662

AN:

1461822

Hom.:

Cov.:

AF XY:

0.000396

AC XY:

288

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0166

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00109

GnomAD4 genome

AF:

0.00483

AC:

736

AN:

152250

Hom.:

Cov.:

AF XY:

0.00465

AC XY:

346

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0170

Gnomad4 AMR

AF:

0.00137

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:

0.00284

Alfa

AF:

0.000879

Hom.:

Bravo

AF:

0.00578

ESP6500AA

AF:

0.0161

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00150

AC:

182

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Cardiac arrhythmia, ankyrin-B-related

Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2016

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. -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 06, 2017

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2015

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

0.15

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

Cadd

Benign

Dann

Benign

0.90

DEOGEN2

Benign

0.33

T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

0.92

D;D;D;D;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.97

N;N

REVEL

Benign

0.080

Sift

Benign

0.10

T;T

Sift4G

Benign

0.43

T;T

Vest4

0.17

MVP

0.40

MPC

0.11

ClinPred

0.0019

GERP RS

2.2

Varity_R

0.064

gMVP

0.029

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