chr17-21702913-C-T

Position:

• chr17-21702913-C-T

Variant summary

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

The NM_001194958.2(KCNJ18):​c.127C>T​(p.Arg43Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,594,154 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 0.00037 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: KCNJ18 NM_001194958.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34

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=0.15519297).
• BS2: High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ18	NM_001194958.2	c.127C>T	p.Arg43Cys	missense_variant	3/3	ENST00000567955.3	NP_001181887.2
KCNJ18	XM_005276919.4	c.433C>T	p.Arg145Cys	missense_variant	2/2		XP_005276976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ18	ENST00000567955.3	c.127C>T	p.Arg43Cys	missense_variant	3/3	1	NM_001194958.2	ENSP00000457807.2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152120 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000562 AC: 811 AN: 1441916 Hom.: 0 Cov.: 72 AF XY: 0.000597 AC XY: 428 AN XY: 716336

Gnomad4 AFR exome AF: 0.000271

Gnomad4 AMR exome AF: 0.0000473

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000398

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.0000419

Gnomad4 NFE exome AF: 0.000583

Gnomad4 OTH exome AF: 0.000635

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152238 Hom.: 0 Cov.: 34 AF XY: 0.000470 AC XY: 35 AN XY: 74426

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000422 Hom.: 0

Bravo AF: 0.000325

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000329 AC: 40

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.80	T
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.0	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.44
MVP		0.28
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.70
gMVP		0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs527236151; hg19: chr17-21318781;