dbSNP rs527236157: KCNJ18:p.Gln407* (chr17-21704005-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001194958.2(KCNJ18):c.1219C>T(p.Gln407*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00263 in 1,594,896 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0075 ( 14 hom., cov: 35)

Exomes 𝑓: 0.0021 ( 34 hom. )

Consequence

KCNJ18
NM_001194958.2 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.83

Publications

2 publications found

Variant links:

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]

KCNJ18 Gene-Disease associations (from GenCC):

thyrotoxic periodic paralysis, susceptibility to, 2
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics

KCNJ18 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00748 (1140/152342) while in subpopulation AFR AF = 0.0186 (774/41578). AF 95% confidence interval is 0.0175. There are 14 homozygotes in GnomAd4. There are 571 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAd4 at 1140 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001194958.2. 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
	KCNJ18	NM_001194958.2	MANE Select	c.1219C>T	p.Gln407*	stop_gained	Exon 3 of 3	NP_001181887.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ18	ENST00000567955.3	TSL:1 MANE Select	c.1219C>T	p.Gln407*	stop_gained	Exon 3 of 3	ENSP00000457807.2

Frequencies

GnomAD3 genomes

AF:

0.00746

AC:

1136

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00132

Gnomad OTH

AF:

0.0158

GnomAD4 exome

AF:

0.00212

AC:

3052

AN:

1442554

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

1454

AN XY:

715752

show subpopulations

African (AFR)

AF:

0.0197

AC:

651

AN:

33124

American (AMR)

AF:

0.00774

AC:

341

AN:

44070

Ashkenazi Jewish (ASJ)

AF:

0.0162

AC:

412

AN:

25390

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39436

South Asian (SAS)

AF:

0.0000354

AC:

AN:

84774

European-Finnish (FIN)

AF:

0.0000625

AC:

AN:

48024

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

4876

European-Non Finnish (NFE)

AF:

0.00114

AC:

1259

AN:

1103238

Other (OTH)

AF:

0.00527

AC:

314

AN:

59622

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

200

399

599

798

998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00748

AC:

1140

AN:

152342

Hom.:

Cov.:

AF XY:

0.00766

AC XY:

571

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0186

AC:

774

AN:

41578

American (AMR)

AF:

0.0120

AC:

184

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00132

AC:

AN:

68038

Other (OTH)

AF:

0.0156

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

121

182

242

303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00534

Hom.:

Bravo

AF:

0.00878

ExAC

AF:

0.00267

AC:

324

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.93

PhyloP100

4.8

Vest4

0.052

GERP RS

3.7

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over