17-70175135-C-G

Variant names:

• chr17-70175135-C-G
• rs67120636
• NM_000891.3:c.96C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000891.3(KCNJ2):​c.96C>G​(p.Asn32Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N32N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ2 NM_000891.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.02

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 79) in uniprot entity KCNJ2_HUMAN there are 30 pathogenic changes around while only 4 benign (88%) in NM_000891.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCNJ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 51 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 2.7459 (below the threshold of 3.09). Trascript score misZ: 3.9347 (above the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome, short QT syndrome, Andersen-Tawil syndrome, familial atrial fibrillation, short QT syndrome type 3, catecholaminergic polymorphic ventricular tachycardia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33864477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ2	NM_000891.3	c.96C>G	p.Asn32Lys	missense_variant	Exon 2 of 2	ENST00000243457.4	NP_000882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4	c.96C>G	p.Asn32Lys	missense_variant	Exon 2 of 2	1	NM_000891.3	ENSP00000243457.2
KCNJ2	ENST00000535240.1	c.96C>G	p.Asn32Lys	missense_variant	Exon 2 of 2	1		ENSP00000441848.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Uncertain:1

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 32 of the KCNJ2 protein (p.Asn32Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNJ2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.93	.;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		-1.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.28
Sift	Benign	0.032	D;D
Sift4G	Benign	0.41	T;T
Polyphen		0.98	D;D
Vest4		0.62
MutPred		0.67		Gain of methylation at N32 (P = 0.0121);Gain of methylation at N32 (P = 0.0121);
MVP		0.17
MPC		2.1
ClinPred		0.96	D
GERP RS		-8.4
Varity_R		0.30
gMVP		0.98
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

dbSNP: rs67120636; hg19: chr17-68171276;