rs1320716221

Variant names:

• chr17-21703629-C-G
• rs1320716221
• NM_001194958.2:c.843C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-21703629-C-G
• chr17-21703629-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001194958.2(KCNJ18):​c.843C>G​(p.Phe281Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,610,442 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: KCNJ18 NM_001194958.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0120
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023442388).
• BS2: High AC in GnomAd4 at 275 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.843C>G	p.Phe281Leu	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.843C>G	p.Phe281Leu	missense	Exon 3 of 3	ENSP00000457807.2	B7U540

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 275 AN: 152104 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00156 AC: 2269 AN: 1458220 Hom.: 2 Cov.: 84 AF XY: 0.00149 AC XY: 1081 AN XY: 724706

African (AFR) AF: 0.000300 AC: 10 AN: 33332

American (AMR) AF: 0.00287 AC: 128 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.000958 AC: 25 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.000642 AC: 34 AN: 52924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00179 AC: 1985 AN: 1109486

Other (OTH) AF: 0.00144 AC: 87 AN: 60278

GnomAD4 genome AF: 0.00181 AC: 275 AN: 152222 Hom.: 1 Cov.: 34 AF XY: 0.00180 AC XY: 134 AN XY: 74434

African (AFR) AF: 0.000579 AC: 24 AN: 41486

American (AMR) AF: 0.00399 AC: 61 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00263 AC: 179 AN: 68026

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00143 AC: 174

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	16
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	0.043	D
PhyloP100		-0.012
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0060	D
Vest4		0.48
MutPred		0.69		Gain of disorder (P = 0.1433)
MVP		0.048
ClinPred		0.12	T
GERP RS		-7.5
gMVP		0.40

Splicing

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

Other links and lift over

dbSNP: rs1320716221; hg19: chr17-21319497;