17-21703400-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP4 BS2

The NM_001194958.2(KCNJ18):c.614G>A(p.Arg205His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 49)
  • Exomes 𝑓: 0.000018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNJ18 NM_001194958.2 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• 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 -4 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, phyloP100way_vertebrate, PrimateAI, PROVEAN [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.31878924).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ18	NM_001194958.2	c.614G>A	p.Arg205His	missense_variant	3/3	ENST00000567955.3
KCNJ18	XM_005276919.4	c.920G>A	p.Arg307His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ18	ENST00000567955.3	c.614G>A	p.Arg205His	missense_variant	3/3	1	NM_001194958.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152288 Hom.: 0 Cov.: 49

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000185 AC: 27 AN: 1459464 Hom.: 0 Cov.: 149 AF XY: 0.0000207 AC XY: 15 AN XY: 726030

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000591 AC: 9 AN: 152406 Hom.: 0 Cov.: 49 AF XY: 0.0000537 AC XY: 4 AN XY: 74532

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Thyrotoxic periodic paralysis, susceptibility to, 2 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 08, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	28
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.75	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.010	D
Vest4		0.46
MVP		0.29
ClinPred		0.73	D
GERP RS		5.3
Varity_R		0.64
gMVP		0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs672601244; hg19: chr17-21319268;