chr17-70175238-C-T

Variant names:

• chr17-70175238-C-T
• rs104894580
• NM_000891.3:c.199C>T
• KCNJ2 p.Arg67Trp

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+7 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 7 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO4_SupportingO6_SupportingO7_ModerateO8_Supporting

The NM_000891.3(KCNJ2):c.199C>T (p.Arg67Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene KCNJ2 is a known oncogene (CancerMine: 2 oncogene, 1 driver citations). The gene KCNJ2 is a cancer driver gene (CancerMine: 2 oncogene, 1 driver citations). 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) The variant has been observed in cBioPortal in 8 samples across 7 studies and 4 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). 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:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNJ2 NM_000891.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:2
• Conservation: PhyloP100: 4.12
• Publications: 33 publications found

Genes affected

KCNJ2 (HGNC:6263): (potassium inwardly rectifying channel subfamily J member 2) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Mutations in this gene have been associated with Andersen syndrome, which is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. [provided by RefSeq, Jul 2008]

KCNJ2 Gene-Disease associations (from GenCC):

• Andersen-Tawil syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• atrial fibrillation, familial, 9

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• short QT syndrome type 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen, G2P
• long QT syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000001, AC = 1 — absent/extremely rare (O3 moderate [+2])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=8 | studies=7 | cancer types=4 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Moderate: ≥10 same AA change, or strong functional domain signal; No cancerhotspots.org hit at this position; UniProt domain: 12 pathogenic, 5 benign (OR vs. background: 11.4).; ±8 AA neighbourhood: 5 pathogenic, 1 benign (OR vs. background: 18.3); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 3.94 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNJ2 NM_000891.3	MANE Select	c.199C>T p.Arg67Trp	missense	Exon 2 of 2	Prot: NP_000882.1 UniProt:

KCNJ2 NM_000891.3

MANE Select

HGVSc / HGVSpc.199C>Tp.Arg67Trp

Exon rankExon 2 of 2

missense

Prot: NP_000882.1UniProt: P63252

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNJ2 ENST00000243457.4	TSL:1MANE Select	c.199C>T p.Arg67Trp	missense	Exon 2 of 2	Prot: ENSP00000243457.2 UniProt:
	KCNJ2 ENST00000535240.1	TSL:1	c.199C>T p.Arg67Trp	missense	Exon 2 of 2	Prot: ENSP00000441848.1 UniProt:
	KCNJ2 ENST00000854891.1		c.199C>T p.Arg67Trp	missense	Exon 3 of 3	Prot: ENSP00000524950.1 UniProt:

KCNJ2 ENST00000243457.4

TSL:1MANE Select

HGVSc / HGVSpc.199C>Tp.Arg67Trp

Exon rankExon 2 of 2

missense

Prot: ENSP00000243457.2UniProt: P63252

KCNJ2 ENST00000535240.1

TSL:1

HGVSc / HGVSpc.199C>Tp.Arg67Trp

Exon rankExon 2 of 2

missense

Prot: ENSP00000441848.1UniProt: P63252

KCNJ2 ENST00000854891.1

HGVSc / HGVSpc.199C>Tp.Arg67Trp

Exon rankExon 3 of 3

missense

Prot: ENSP00000524950.1UniProt: P63252

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461892	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:203910	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Andersen Tawil syndrome (5)
3	-	-	not provided (3)
1	-	-	Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 (1)
1	-	-	Andersen Tawil syndrome;C1865018:Short QT syndrome type 3;C3151431:Atrial fibrillation, familial, 9 (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	not specified (1)
-	-	-	Congenital long QT syndrome (1)

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

Showing 28 of 28 scores

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

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs104894580;

hg19: chr17-68171379;

COSMIC: COSV54660398;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar