NM_000891.3:c.199C>T
Variant summary
The NM_000891.3(KCNJ2):c.199C>T (p.Arg67Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,892 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002038508: "its effect of p.R67W variatn is described in in vitro studies (PS3 criteria)"" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R67Q: Pathogenic/Likely_pathogenic (ClinVar VariationId 67560, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R67= (synonymous): Likely_benign (ClinVar VariationId 2566714, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.
Frequency
Consequence
NM_000891.3 missense
Scores
Clinical Significance
Conservation
Publications
- Andersen-Tawil syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- atrial fibrillation, familial, 9Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
- short QT syndrome type 3Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
- short QT syndromeInheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- familial atrial fibrillationInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- catecholaminergic polymorphic ventricular tachycardiaInheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen, G2P
- long QT syndromeInheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
- congenital heart diseaseInheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen
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Classification according to ACMG Germline Pathogenicity v2019
Our verdict: Pathogenic. The variant received 19 points.
| Apply | Criterion Code & Title / Strength | Rationale / Clinical Context | |
|---|---|---|---|
| PS3Functional studies show damaging effect | Well-established functional study supports damaging effect (PS3); SCV002038508: "its effect of p.R67W variatn is described in in vitro studies (PS3 criteria)"; SCV000223534: Published functional studies demonstrate the variant alters channel function (Donaldson et al., 2003; Andelfinger et al., 2002); SCV000955346: Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 12148092, 20713726).; SCV001158053: Functional analyses of the variant protein show loss of channel function, dominant negative effects, and decreased PIP2 binding that inhibits channel function (Andelfinger 2002, Donaldson 2003).; SCV002717713: Limited functional studies demonstrated significant impact on potassium channel function (Andelfinger G et al. Am. J. Hum. Genet., 2002 Sep;71:663-8). | ||
| PM1Mutational hot spot or critical domain | UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 12 pathogenic, 5 benign rare missense variants (OR vs. background: 11.4).; ±8 AA neighbourhood: 5 pathogenic, 1 benign (OR vs. background: 18.3). | ||
| PM2Absent/extremely low in population databases | Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate. | ||
| PM5Novel missense at known pathogenic residue | Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R67Q: Pathogenic/Likely_pathogenic (ClinVar VariationId 67560, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R67= (synonymous): Likely_benign (ClinVar VariationId 2566714, 1 star) | ||
| PP2Missense in gene with low missense rate | Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 3.943). ClinVar shows strong pathogenic missense enrichment: 64 P/LP and 16 B/LB missense entries (ratio 4.0×). | ||
| PP3Computational evidence supports damaging effect | Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong). | ||
| PP5Reputable source reports pathogenic | ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (11/11 total P/LP). |
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_000891.3. You can select a different transcript below to see updated classification assignments.
RefSeq Transcripts
Ensembl Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
KCNJ2 | TSL:1MANE Select | c.199C>T p.Arg67Trp | missense | Exon 2 of 2 | Prot: ENSP00000243457.2 UniProt: | |
KCNJ2 | TSL:1 | c.199C>T p.Arg67Trp | missense | Exon 2 of 2 | Prot: ENSP00000441848.1 UniProt: | |
KCNJ2 | c.199C>T p.Arg67Trp | missense | Exon 3 of 3 | Prot: ENSP00000524950.1 UniProt: |
Frequencies
Allele frequencies (AF), counts (AC/AN), homozygotes and coverage
| Source / population | AF | AC | Hom | AN | Coverage |
|---|---|---|---|---|---|
Global population databases 4 sources | |||||
GnomAD3 genomes | Cov:32 | ||||
GnomAD4 exome | AF: 6.84e-7 | AC:1 | Hom:0 | AN:1461892 | Cov:31 |
GnomAD4 genome | Cov:32 | ||||
ALFA (dbGaP/dbSNP Allele Frequency Aggregator) | AF: 0.00 | AC:0 | Hom:0 | AN:203910 | |
ClinVar
Computational Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
AlphaGenome AVI | Pathogenic | 24 | |
AlphaMissense | Pathogenic | 0.73 | |
BayesDel_addAF | Pathogenic | 0.53 | D |
BayesDel_noAF | Pathogenic | 0.53 | |
CADD | Pathogenic | 27 | |
DANN | Uncertain | 1.0 | |
DEOGEN2 | Pathogenic | 0.98 | D |
Eigen | Uncertain | 0.55 | |
Eigen_PC | Uncertain | 0.43 | |
FATHMM_MKL | Uncertain | 0.94 | D |
FuncVEP CTI | Pathogenic | 1.0 | |
GPN-Star LLR | N/A | -9.7 | |
GPN-Star score | N/A | 9.5 | |
LIST_S2 | Pathogenic | 1.0 | D |
M_CAP | Pathogenic | 0.55 | D |
MetaRNN | Pathogenic | 0.99 | D |
MetaSVM | Pathogenic | 1.1 | D |
Mutation Taster | N/A | 1/99 | disease causing (ClinVar) |
MutationAssessor | Pathogenic | 3.7 | H |
PhyloP100 | Uncertain | 4.1 | |
popEVE | Benign | -4.4 | |
PrimateAI | Pathogenic | 0.93 | D |
PROVEAN | Pathogenic | -6.9 | D |
REVEL | Pathogenic | 0.94 | |
Sift | Pathogenic | 0.0 | D |
Sift4G | Pathogenic | 0.0 | D |
Varity_R | N/A | 0.86 | |
VESM-3B | Benign | -11 |
Splicing Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
Pangolin (max) | Benign | 0.010 | |
SpliceAI score (max) | Benign | 0.0 | Details are displayed if max score is > 0.2 |
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.