12-21765816-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004982.4(KCNJ8):c.1182G>C(p.Arg394Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNJ8 NM_004982.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.315

Genes affected

KCNJ8 (HGNC:6269): (potassium inwardly rectifying channel subfamily J member 8) 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, is controlled by G-proteins. Defects in this gene may be a cause of J-wave syndromes and sudden infant death syndrome (SIDS). [provided by RefSeq, May 2012]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNJ8
• BP4: Computational evidence support a benign effect (MetaRNN=0.15686077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ8	NM_004982.4	c.1182G>C	p.Arg394Ser	missense_variant	3/3	ENST00000240662.3
LOC105369689	XR_007063241.1	n.631+5731C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ8	ENST00000240662.3	c.1182G>C	p.Arg394Ser	missense_variant	3/3	1	NM_004982.4	P1
	ENST00000542489.1	n.107-540C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461688 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2018

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This variant has not been reported in the literature in individuals with KCNJ8-related disease. ClinVar contains an entry for this variant (Variation ID: 180388). This sequence change replaces arginine with serine at codon 394 of the KCNJ8 protein (p.Arg394Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

The p.R394S variant (also known as c.1182G>C), located in coding exon 2 of the KCNJ8 gene, results from a G to C substitution at nucleotide position 1182. The arginine at codon 394 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 13, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	15
Dann	Uncertain	0.97
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.28
Sift	Benign	0.18	T
Sift4G	Benign	0.75	T
Polyphen		0.42	B
Vest4		0.29
MutPred		0.25		Gain of phosphorylation at R394 (P = 0.0129);
MVP		0.58
MPC		1.2
ClinPred		0.15	T
GERP RS		0.87
Varity_R		0.20
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs730880120; hg19: chr12-21918750;