chr17-21702905-G-A

Variant names:

• chr17-21702905-G-A
• rs1267282483
• NM_001194958.2:c.119G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001194958.2(KCNJ18):​c.119G>A​(p.Arg40His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 1,531,558 control chromosomes in the GnomAD database, including 125,577 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (12875 hom., cov: 33)
  • Exomes 𝑓: 0.43 (112702 hom.)
• Consequence: KCNJ18 NM_001194958.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.37
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060729682).
• BP6: Variant 17-21702905-G-A is Benign according to our data. Variant chr17-21702905-G-A is described in ClinVar as Benign. ClinVar VariationId is 3061031.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

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.119G>A	p.Arg40His	missense	Exon 3 of 3	NP_001181887.2	B7U540

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ18	ENST00000567955.3	TSL:1 MANE Select	c.119G>A	p.Arg40His	missense	Exon 3 of 3	ENSP00000457807.2	B7U540

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59236 AN: 149776 Hom.: 12868 Cov.: 33

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.787

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.415

GnomAD4 exome AF: 0.429 AC: 592790 AN: 1381654 Hom.: 112702 Cov.: 73 AF XY: 0.434 AC XY: 297985 AN XY: 686120

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.180 AC: 5917 AN: 32792

American (AMR) AF: 0.514 AC: 20906 AN: 40670

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 10001 AN: 25194

East Asian (EAS) AF: 0.829 AC: 30572 AN: 36896

South Asian (SAS) AF: 0.564 AC: 45637 AN: 80890

European-Finnish (FIN) AF: 0.397 AC: 17985 AN: 45304

Middle Eastern (MID) AF: 0.416 AC: 2328 AN: 5590

European-Non Finnish (NFE) AF: 0.411 AC: 434465 AN: 1056608

Other (OTH) AF: 0.433 AC: 24979 AN: 57710

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.395 AC: 59256 AN: 149904 Hom.: 12875 Cov.: 33 AF XY: 0.398 AC XY: 29178 AN XY: 73222

African (AFR) AF: 0.202 AC: 8374 AN: 41372

American (AMR) AF: 0.481 AC: 7181 AN: 14918

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1418 AN: 3446

East Asian (EAS) AF: 0.788 AC: 3767 AN: 4780

South Asian (SAS) AF: 0.601 AC: 2792 AN: 4648

European-Finnish (FIN) AF: 0.419 AC: 4392 AN: 10490

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.447 AC: 29959 AN: 66976

Other (OTH) AF: 0.417 AC: 872 AN: 2090

Alfa AF: 0.407 Hom.: 1057

Bravo AF: 0.399

ESP6500AA AF: 0.142 AC: 626

ESP6500EA AF: 0.307 AC: 2643

ExAC AF: 0.350 AC: 42506

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	KCNJ18-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DEOGEN2	Benign	0.038	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.89	T
PhyloP100		2.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N
Sift	Benign	0.063	T
Sift4G	Uncertain	0.039	D
Vest4		0.18
ClinPred		0.029	T
GERP RS		5.3
gMVP		0.55

Splicing

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

Other links and lift over

dbSNP: rs1267282483; hg19: chr17-21318773;