12-21765773-T-C

Variant names:

• chr12-21765773-T-C
• NM_004982.4:c.1225A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004982.4(KCNJ8):​c.1225A>G​(p.Lys409Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ8 NM_004982.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66

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]

ENSG00000255644 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ8	NM_004982.4	c.1225A>G	p.Lys409Glu	missense_variant	Exon 3 of 3	ENST00000240662.3	NP_004973.1
LOC105369689	XR_007063241.1	n.631+5688T>C		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ8	ENST00000240662.3	c.1225A>G	p.Lys409Glu	missense_variant	Exon 3 of 3	1	NM_004982.4	ENSP00000240662.2

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

Cardiovascular phenotype Uncertain:1

Jan 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K409E variant (also known as c.1225A>G), located in coding exon 2 of the KCNJ8 gene, results from an A to G substitution at nucleotide position 1225. The lysine at codon 409 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.97	L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.11	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.011	D
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.66
MutPred		0.29		Loss of methylation at K409 (P = 0.0025);
MVP		0.80
MPC		2.5
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.20
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-21918707;