NM_000891.3:c.199_201delCGGinsAGA

Variant names:

• chr17-70175238-CGG-AGA
• NM_000891.3:c.199_201delCGGinsAGA
• KCNJ2 p.68

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000891.3(KCNJ2):c.199_201delCGGinsAGA (p.68) variant causes a synonymous change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 10.00). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ2 NM_000891.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 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: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

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.199_201delCGGinsAGA p.68	synonymous	N/A	Prot: NP_000882.1 UniProt:

KCNJ2 NM_000891.3

MANE Select

HGVSc / HGVSpc.199_201delCGGinsAGAp.68

Exon rankN/A

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.199_201delCGGinsAGA p.68	synonymous	N/A	Prot: ENSP00000243457.2 UniProt:
	KCNJ2 ENST00000535240.1	TSL:1	c.199_201delCGGinsAGA p.68	synonymous	N/A	Prot: ENSP00000441848.1 UniProt:
	KCNJ2 ENST00000854891.1		c.199_201delCGGinsAGA p.68	synonymous	N/A	Prot: ENSP00000524950.1 UniProt:

KCNJ2 ENST00000243457.4

TSL:1MANE Select

HGVSc / HGVSpc.199_201delCGGinsAGAp.68

Exon rankN/A

synonymous

Prot: ENSP00000243457.2UniProt: P63252

KCNJ2 ENST00000535240.1

TSL:1

HGVSc / HGVSpc.199_201delCGGinsAGAp.68

Exon rankN/A

synonymous

Prot: ENSP00000441848.1UniProt: P63252

KCNJ2 ENST00000854891.1

HGVSc / HGVSpc.199_201delCGGinsAGAp.68

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	10

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr17-68171379;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar