rs761620495
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_001148.6(ANK2):c.868G>A(p.Gly290Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,710 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
ANK2
NM_001148.6 missense
NM_001148.6 missense
Scores
6
11
Clinical Significance
Conservation
PhyloP100: 4.44
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 Likely_benign. Variant got -4 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, ANK2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3265073).
BS2
?
High AC in GnomAdExome4 at 30 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANK2 | NM_001148.6 | c.868G>A | p.Gly290Ser | missense_variant | 9/46 | ENST00000357077.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANK2 | ENST00000357077.9 | c.868G>A | p.Gly290Ser | missense_variant | 9/46 | 1 | NM_001148.6 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152064Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
1
AN:
152064
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251416Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
GnomAD3 exomes
AF:
AC:
5
AN:
251416
Hom.:
AF XY:
AC XY:
1
AN XY:
135874
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461646Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727128
GnomAD4 exome
AF:
AC:
30
AN:
1461646
Hom.:
Cov.:
31
AF XY:
AC XY:
10
AN XY:
727128
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74252
GnomAD4 genome
?
AF:
AC:
1
AN:
152064
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74252
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ExAC
?
AF:
AC:
3
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 03, 2021 | In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs761620495, ExAC <0.01%) but has not been reported in the literature in individuals with an ANK2-related disease. This sequence change replaces glycine with serine at codon 290 of the ANK2 protein (p.Gly290Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N;.
REVEL
Benign
Sift
Benign
D;T;T;T;T;T;T;.
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
0.60, 0.26, 0.99
.;.;P;.;B;D;.;.
Vest4
0.28, 0.28, 0.44, 0.54
MutPred
0.53
.;.;.;.;Gain of MoRF binding (P = 0.0968);Gain of MoRF binding (P = 0.0968);Gain of MoRF binding (P = 0.0968);.;
MVP
MPC
1.3
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at