rs759275920
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001148.6(ANK2):c.2713G>A(p.Asp905Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
ANK2
NM_001148.6 missense
NM_001148.6 missense
Scores
3
8
8
Clinical Significance
Conservation
PhyloP100: 7.75
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAdExome4 at 25 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152072Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251442Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135888
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GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461712Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14AN XY: 727158
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152072Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74272
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Apr 21, 2014 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. The variant is novel. This is a semi-conservative amino acid substitution. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. No missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014). The variant was reported online in 2 of 61,359 individuals in the Exome Aggregation Consortium dataset, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of December 1st, 2014). 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). There are also several other variants listed in ExAC at nearby residues with similar frequencies. In addition, a different variant at the same residue, p.Asp905His, is present in 1 of 61,359 individuals. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2014 | p.Asp905Asn (GAC>AAC): c.2713 G>A in exon 25 of the ANK2 gene (NM_001148.4). The D905N variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The D905N variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D905N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no missense mutations in nearby residues have been reported in association with LQTS, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s). - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 20, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANK2 protein function. ClinVar contains an entry for this variant (Variation ID: 190596). This variant has not been reported in the literature in individuals affected with ANK2-related conditions. This variant is present in population databases (rs759275920, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 905 of the ANK2 protein (p.Asp905Asn). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;T;.;T;.;D;T;T;T
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;.;.;.;M;M;.;.;.
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;.;D
REVEL
Uncertain
Sift
Benign
T;D;D;D;D;D;D;.;D
Sift4G
Benign
T;T;T;T;T;D;D;T;T
Polyphen
0.0040, 0.31, 1.0, 0.99
.;.;B;.;B;D;.;.;D
Vest4
0.78, 0.86, 0.61, 0.59, 0.73
MutPred
0.40
.;.;.;.;Gain of glycosylation at S901 (P = 0.0025);Gain of glycosylation at S901 (P = 0.0025);Gain of glycosylation at S901 (P = 0.0025);.;.;
MVP
MPC
1.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at