rs527236154

Positions:

• chr17-21703288-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001194958.2(KCNJ18):​c.502G>A​(p.Val168Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000385 in 1,608,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: KCNJ18 NM_001194958.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.25

Genes affected

KCNJ18 (HGNC:39080): (potassium inwardly rectifying channel subfamily J member 18) This gene encodes a member of the inwardly rectifying potassium channel family. Transcription of this locus is regulated by thyroid hormone, and the encoded protein plays a role in resting membrane potential maintenance. Mutations in this locus have been associated with thyrotoxic hypokalemic periodic paralysis. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23557478).
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ18	NM_001194958.2	c.502G>A	p.Val168Met	missense_variant	3/3	ENST00000567955.3
KCNJ18	XM_005276919.4	c.808G>A	p.Val270Met	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ18	ENST00000567955.3	c.502G>A	p.Val168Met	missense_variant	3/3	1	NM_001194958.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152136 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000364 AC: 53 AN: 1456494 Hom.: 0 Cov.: 128 AF XY: 0.0000345 AC XY: 25 AN XY: 723846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000657

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000997

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152252 Hom.: 0 Cov.: 35 AF XY: 0.0000269 AC XY: 2 AN XY: 74432

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.70	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.88	N
Sift	Benign	0.053	T
Sift4G	Uncertain	0.049	D
Vest4		0.55
MVP		0.36
ClinPred		0.25	T
GERP RS		5.3
Varity_R		0.32
gMVP		0.71

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs527236154; hg19: chr17-21319156;