chr22-38426909-C-G

Variant names:

• chr22-38426909-C-G
• rs779001054
• NM_152868.3:c.1224G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152868.3(KCNJ4):​c.1224G>C​(p.Lys408Asn) 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 1,460,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNJ4 NM_152868.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97
• Publications: 0 publications found

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]

ENSG00000228620 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15667874).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152868.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ4	NM_152868.3	MANE Select	c.1224G>C	p.Lys408Asn	missense	Exon 2 of 2	NP_690607.1	P48050
	KCNJ4	NM_004981.2		c.1224G>C	p.Lys408Asn	missense	Exon 2 of 2	NP_004972.1	P48050

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ4	ENST00000303592.3	TSL:1 MANE Select	c.1224G>C	p.Lys408Asn	missense	Exon 2 of 2	ENSP00000306497.3	P48050
	KCNJ4	ENST00000940563.1		c.1224G>C	p.Lys408Asn	missense	Exon 2 of 2	ENSP00000610622.1
	KCNJ4	ENST00000947103.1		c.1224G>C	p.Lys408Asn	missense	Exon 2 of 2	ENSP00000617162.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249534 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460692 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726664

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111880

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.23
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.18
Sift	Benign	0.23	T
Sift4G	Benign	0.40	T
Polyphen		0.072	B
Vest4		0.32
MutPred		0.24		Loss of ubiquitination at K408 (P = 0.0022)
MVP		0.60
MPC		1.6
ClinPred		0.069	T
GERP RS		3.3
Varity_R		0.071
gMVP		0.62
Mutation Taster		=88/12	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

Other links and lift over

dbSNP: rs779001054; hg19: chr22-38822914;