rs746436835
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001148.6(ANK2):c.2063T>A(p.Ile688Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
ANK2
NM_001148.6 missense
NM_001148.6 missense
Scores
3
11
5
Clinical Significance
Conservation
PhyloP100: 3.48
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.791
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152124
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: 0.0000239 AC: 6AN: 251066Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135676
GnomAD3 exomes
AF:
AC:
6
AN:
251066
Hom.:
AF XY:
AC XY:
4
AN XY:
135676
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: 0.00000205 AC: 3AN: 1461698Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727152
GnomAD4 exome
AF:
AC:
3
AN:
1461698
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727152
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 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74292
GnomAD4 genome
AF:
AC:
1
AN:
152124
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74292
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
2
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Apr 21, 2017 | The patient is a 13-year-old female with a QTc of up to 509 msec on EKG. She had genetic testing for LQTS with the Invitae laboratory. The following 17 genes were evaluated for sequence changes and exonic deletions/duplications: AKAP9, ANK2, CACNA1C, CALM1, CALM2, CALM3, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1, TRDN. The lab reported two variants: • p.Arg366Gln (R366Q; c.1097G>A) in the KCNQ1 gene (pathogenic, and diagnostic of LQTS type 1) • p.Ile688Asn (I688N; c.2063T>A) in the ANK2 gene p.Ile688Asn (I688N; c.2063T>A) in exon 18 of the ANK2 gene (NM_001148.4; ENST00000357077.8) Chromosome location: 4:114204012 T / A Based on the information reviewed below, we classify this as a Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This variant has not been reported in the literature in association with disease, but it is present in population databases—exclusively in people with this patient’s ethnicity. For this reason, we think it is more likely to be benign. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Isoleucine with a polar Asparagine. Isoleucine at this location is not conserved across vertebrate species, and may be replaced by another nonpolar amino acid such as Valine or Alanine. There are no clearly Pathogenic or Likely Pathogenic variants listed in ClinVar within 10 amino acids of this codon as of 4/21/2017. According to the Invitae report, 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant was reported online in 7 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 7/9,432 East Asians (for the highest allele frequency: 0.037%). It is not reported in any other ancestry group. Our patient’s ancestry is from Vietnam. The phenotype of the individuals in gnomAD 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. The curators made an effort to exclude individuals with severe pediatric diseases. (There is 1 Caucasian individual in gnomAD with another variant at this site: p.Ile688Val.) - |
Long QT syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 05, 2017 | This sequence change replaces isoleucine with asparagine at codon 688 of the ANK2 protein (p.Ile688Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs746436835, ExAC 0.02%) but has not been reported in the literature in individuals with a ANK2-related disease. ClinVar contains an entry for this variant (Variation ID: 264395). 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. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 03, 2015 | The p.I688N variant (also known as c.2063T>A), located in coding exon 18 of the ANK2 gene, results from a T to A substitution at nucleotide position 2063. The isoleucine at codon 688 is replaced by asparagine, an amino acid with dissimilar properties. Based on data from ExAC, the A allele has an overall frequency of approximately 0.001% (2/120940). The highest observed frequency was 0.02% (2/8632) of East Asian alleles (Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [Accessed September 30, 2015]). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;.;T;.;D;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
.;.;.;.;M;M;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;.
REVEL
Uncertain
Sift
Benign
T;D;D;T;D;D;D;.
Sift4G
Benign
T;D;D;D;D;D;D;D
Polyphen
0.82, 0.98, 1.0
.;.;P;.;D;D;.;.
Vest4
0.81, 0.78, 0.81, 0.87
MutPred
0.72
.;.;.;.;Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);.;
MVP
MPC
2.0
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