17-70175238-C-A

Variant names:

• chr17-70175238-C-A
• rs104894580
• NM_000891.3:c.199C>A
• KCNJ2 p.Arg67Arg

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP6_ModerateBP7

The NM_000891.3(KCNJ2):c.199C>A (p.Arg67Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,461,892 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNJ2 NM_000891.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.12
• Publications: 43 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000003 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

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>A p.Arg67Arg	synonymous	Exon 2 of 2	Prot: NP_000882.1 UniProt:

KCNJ2 NM_000891.3

MANE Select

HGVSc / HGVSpc.199C>Ap.Arg67Arg

Exon rankExon 2 of 2

synonymous

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>A p.Arg67Arg	synonymous	Exon 2 of 2	Prot: ENSP00000243457.2 UniProt:
	KCNJ2 ENST00000535240.1	TSL:1	c.199C>A p.Arg67Arg	synonymous	Exon 2 of 2	Prot: ENSP00000441848.1 UniProt:
	KCNJ2 ENST00000854891.1		c.199C>A p.Arg67Arg	synonymous	Exon 3 of 3	Prot: ENSP00000524950.1 UniProt:

KCNJ2 ENST00000243457.4

TSL:1MANE Select

HGVSc / HGVSpc.199C>Ap.Arg67Arg

Exon rankExon 2 of 2

synonymous

Prot: ENSP00000243457.2UniProt: P63252

KCNJ2 ENST00000535240.1

TSL:1

HGVSc / HGVSpc.199C>Ap.Arg67Arg

Exon rankExon 2 of 2

synonymous

Prot: ENSP00000441848.1UniProt: P63252

KCNJ2 ENST00000854891.1

HGVSc / HGVSpc.199C>Ap.Arg67Arg

Exon rankExon 3 of 3

synonymous

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
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251478	Cov:
GnomAD4 exome	AF: 0.00000137	AC:2	Hom:0	AN:1461892	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00 *	0	1490	0.000139 *	1	7190
SCHEMA(Schizophrenia)	0.00	0	67688	0.00000751	1	133092

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	15
BayesDel_noAF	Benign	-0.25
CADD	Benign	9.1
DANN	Benign	0.54
GPN-Star LLR	N/A	-4.1
GPN-Star score	N/A	4.1
PhyloP100	Uncertain	4.1

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
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: COSV54661717;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar