chr4-113049776-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001148.6(ANK2):​c.48C>G​(p.Phe16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F16F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ANK2
NM_001148.6 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.18
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-AS1 (HGNC:40076): (ANK2 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANK2. . Gene score misZ 1.9641 (greater than the threshold 3.09). Trascript score misZ 4.2513 (greater than threshold 3.09). GenCC has associacion of gene with heart conduction disease, Brugada syndrome, long QT syndrome, complex neurodevelopmental disorder, cardiac arrhythmia, ankyrin-B-related, catecholaminergic polymorphic ventricular tachycardia.
BP4
Computational evidence support a benign effect (MetaRNN=0.105382055).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ANK2NM_001148.6 linkuse as main transcriptc.48C>G p.Phe16Leu missense_variant 1/46 ENST00000357077.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ANK2ENST00000357077.9 linkuse as main transcriptc.48C>G p.Phe16Leu missense_variant 1/461 NM_001148.6 A2Q01484-4
ANK2-AS1ENST00000508959.1 linkuse as main transcriptn.126-14982G>C intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 28, 2023The p.F16L variant (also known as c.48C>G), located in coding exon 1 of the ANK2 gene, results from a C to G substitution at nucleotide position 48. The phenylalanine at codon 16 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.34
BayesDel_addAF
Benign
-0.059
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
18
DANN
Benign
0.87
DEOGEN2
Benign
0.22
T;.;T;T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.75
T;T;T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.11
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.69
.;N;N;.
MutationTaster
Benign
1.0
D;N;N;N
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.38
N;N;N;N
REVEL
Uncertain
0.31
Sift
Benign
0.35
T;T;T;T
Sift4G
Benign
0.65
T;T;T;T
Polyphen
0.0, 0.58
.;B;P;.
Vest4
0.24, 0.24, 0.30
MutPred
0.27
Gain of glycosylation at S20 (P = 0.0016);Gain of glycosylation at S20 (P = 0.0016);Gain of glycosylation at S20 (P = 0.0016);Gain of glycosylation at S20 (P = 0.0016);
MVP
0.62
MPC
0.67
ClinPred
0.25
T
GERP RS
3.5
Varity_R
0.072
gMVP
0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-113970932; API