22-38426962-C-T

Variant names:

• chr22-38426962-C-T
• rs757178172
• NM_152868.3:c.1171G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152868.3(KCNJ4):​c.1171G>A​(p.Ala391Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 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: 4.46

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1341145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ4	NM_152868.3	c.1171G>A	p.Ala391Thr	missense_variant	Exon 2 of 2	ENST00000303592.3	NP_690607.1
KCNJ4	NM_004981.2	c.1171G>A	p.Ala391Thr	missense_variant	Exon 2 of 2		NP_004972.1
LOC101927183	XR_938252.3	n.306+1990C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ4	ENST00000303592.3	c.1171G>A	p.Ala391Thr	missense_variant	Exon 2 of 2	1	NM_152868.3	ENSP00000306497.3
ENSG00000228620	ENST00000433230.1	n.297-115C>T		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247948 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460494 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1171G>A (p.A391T) alteration is located in exon 2 (coding exon 1) of the KCNJ4 gene. This alteration results from a G to A substitution at nucleotide position 1171, causing the alanine (A) at amino acid position 391 to be replaced by a threonine (T). 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	Benign	0.075
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.90	L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.24
Sift	Benign	0.42	T
Sift4G	Benign	0.57	T
Polyphen		0.0080	B
Vest4		0.16
MutPred		0.29		Gain of glycosylation at A391 (P = 0.0078);
MVP		0.73
MPC		1.3
ClinPred		0.25	T
GERP RS		4.3
Varity_R		0.069
gMVP		0.41

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: rs757178172; hg19: chr22-38822967;