4-113355204-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_001148.6(ANK2):c.6586G>A(p.Gly2196Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. G2196D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001148.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANK2 | NM_001148.6 | c.6586G>A | p.Gly2196Ser | missense_variant | 38/46 | ENST00000357077.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANK2 | ENST00000357077.9 | c.6586G>A | p.Gly2196Ser | missense_variant | 38/46 | 1 | NM_001148.6 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250736Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135478
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461820Hom.: 0 Cov.: 35 AF XY: 0.0000248 AC XY: 18AN XY: 727216
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74302
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 30564305). This variant is present in population databases (rs776545207, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2196 of the ANK2 protein (p.Gly2196Ser). ClinVar contains an entry for this variant (Variation ID: 527020). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. - |
Cardiac arrhythmia, ankyrin-B-related Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 09, 2021 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 02, 2023 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at