rs556640912

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001148.6(ANK2):​c.10976G>A​(p.Arg3659His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,784 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3659L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

ANK2
NM_001148.6 missense

Scores

3
16

Clinical Significance

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

Conservation

PhyloP100: 2.67
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06248951).
BP6
Variant 4-113365126-G-A is Benign according to our data. Variant chr4-113365126-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 457014.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000349 (51/1461776) while in subpopulation AMR AF= 0.000783 (35/44720). AF 95% confidence interval is 0.000578. There are 0 homozygotes in gnomad4_exome. There are 26 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANK2NM_001148.6 linkc.10976G>A p.Arg3659His missense_variant Exon 41 of 46 ENST00000357077.9 NP_001139.3 Q01484-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANK2ENST00000357077.9 linkc.10976G>A p.Arg3659His missense_variant Exon 41 of 46 1 NM_001148.6 ENSP00000349588.4 Q01484-4

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152008
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000119
AC:
30
AN:
251170
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000810
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000349
AC:
51
AN:
1461776
Hom.:
0
Cov.:
32
AF XY:
0.0000358
AC XY:
26
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000783
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
152008
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74250
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000425
Hom.:
0
Bravo
AF:
0.0000907
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Feb 01, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

ANK2-related disorder Benign:1
Apr 15, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Long QT syndrome Benign:1
Nov 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Apr 14, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
0.074
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.30
.;.;T;T;T;.;T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.12
FATHMM_MKL
Benign
0.49
N
LIST_S2
Uncertain
0.92
D;D;D;D;D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.062
T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.15
T
MutationAssessor
Benign
1.1
.;.;L;.;.;.;.
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.27
N;N;N;N;N;N;N
REVEL
Benign
0.16
Sift
Benign
0.25
T;T;T;T;T;T;T
Sift4G
Benign
0.15
T;T;T;T;T;T;T
Polyphen
0.062
B;D;.;.;B;.;.
Vest4
0.12
MutPred
0.32
.;.;.;.;Gain of glycosylation at Y755 (P = 0.0197);.;.;
MVP
0.80
MPC
0.099
ClinPred
0.085
T
GERP RS
3.5
Varity_R
0.025
gMVP
0.20

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.

Other links and lift over

dbSNP: rs556640912; hg19: chr4-114286282; COSMIC: COSV52159451; COSMIC: COSV52159451; API