22-38427164-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_152868.3(KCNJ4):c.969C>G(p.Phe323Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ4 NM_152868.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.285

Genes affected

KCNJ4 (HGNC:6265): (potassium inwardly rectifying channel subfamily J member 4) Several different potassium channels are known to be involved with electrical signaling in the nervous system. One class is activated by depolarization whereas a second class is not. The latter are referred to as inwardly rectifying K+ channels, and they have a greater tendency to allow potassium to flow into the cell rather than out of it. This asymmetry in potassium ion conductance plays a key role in the excitability of muscle cells and neurons. The protein encoded by this gene is an integral membrane protein and member of the inward rectifier potassium channel family. The encoded protein has a small unitary conductance compared to other members of this protein family. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNJ4
• BP4: Computational evidence support a benign effect (MetaRNN=0.35053205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ4	NM_152868.3	c.969C>G	p.Phe323Leu	missense_variant	2/2	ENST00000303592.3
LOC101927183	XR_938252.3	n.306+2192G>C		intron_variant, non_coding_transcript_variant
KCNJ4	NM_004981.2	c.969C>G	p.Phe323Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ4	ENST00000303592.3	c.969C>G	p.Phe323Leu	missense_variant	2/2	1	NM_152868.3	P1
	ENST00000433230.1	n.384G>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.969C>G (p.F323L) alteration is located in exon 2 (coding exon 1) of the KCNJ4 gene. This alteration results from a C to G substitution at nucleotide position 969, causing the phenylalanine (F) at amino acid position 323 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.51
Sift	Benign	0.088	T
Sift4G	Benign	0.58	T
Polyphen		0.35	B
Vest4		0.42
MutPred		0.34		Gain of ubiquitination at K326 (P = 0.0961);
MVP		0.81
MPC		1.5
ClinPred		0.72	D
GERP RS		-2.5
Varity_R		0.35
gMVP		0.86

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: chr22-38823169;