NM_181840.1:c.28A>G

Variant names:

• chr10-117197516-A-G
• rs67346047
• NM_181840.1:c.28A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181840.1(KCNK18):​c.28A>G​(p.Arg10Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0784 in 1,613,430 control chromosomes in the GnomAD database, including 5,758 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (440 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5318 hom.)
• Consequence: KCNK18 NM_181840.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.32
• Publications: 18 publications found

Genes affected

KCNK18 (HGNC:19439): (potassium two pore domain channel subfamily K member 18) Potassium channels play a role in many cellular processes including maintenance of the action potential, muscle contraction, hormone secretion, osmotic regulation, and ion flow. This gene encodes a member of the superfamily of potassium channel proteins containing two pore-forming P domains and the encoded protein functions as an outward rectifying potassium channel. A mutation in this gene has been found to be associated with migraine with aura.[provided by RefSeq, Jan 2011]

KCNK18 Gene-Disease associations (from GenCC):

• migraine, with or without aura, susceptibility to, 13

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015691817).
• BP6: Variant 10-117197516-A-G is Benign according to our data. Variant chr10-117197516-A-G is described in ClinVar as Benign. ClinVar VariationId is 1578252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181840.1. 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
	KCNK18	NM_181840.1	MANE Select	c.28A>G	p.Arg10Gly	missense	Exon 1 of 3	NP_862823.1	Q7Z418

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK18	ENST00000334549.1	TSL:1 MANE Select	c.28A>G	p.Arg10Gly	missense	Exon 1 of 3	ENSP00000334650.1	Q7Z418
	KCNK18	ENST00000850990.1		c.28A>G	p.Arg10Gly	missense	Exon 1 of 3	ENSP00000521071.1

Frequencies

GnomAD3 genomes AF: 0.0634 AC: 9650 AN: 152108 Hom.: 439 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.0971

Gnomad ASJ AF: 0.0866

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0727

Gnomad MID AF: 0.0673

Gnomad NFE AF: 0.0715

Gnomad OTH AF: 0.0631

GnomAD2 exomes AF: 0.0924 AC: 23199 AN: 251152 AF XY: 0.0912

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.0931

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.0820

Gnomad NFE exome AF: 0.0701

Gnomad OTH exome AF: 0.0801

GnomAD4 exome AF: 0.0800 AC: 116910 AN: 1461202 Hom.: 5318 Cov.: 33 AF XY: 0.0808 AC XY: 58741 AN XY: 726928

African (AFR) AF: 0.0114 AC: 381 AN: 33460

American (AMR) AF: 0.150 AC: 6687 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0887 AC: 2318 AN: 26132

East Asian (EAS) AF: 0.164 AC: 6512 AN: 39700

South Asian (SAS) AF: 0.114 AC: 9803 AN: 86220

European-Finnish (FIN) AF: 0.0821 AC: 4383 AN: 53364

Middle Eastern (MID) AF: 0.0627 AC: 342 AN: 5454

European-Non Finnish (NFE) AF: 0.0733 AC: 81514 AN: 1111798

Other (OTH) AF: 0.0824 AC: 4970 AN: 60352

GnomAD4 genome AF: 0.0634 AC: 9645 AN: 152228 Hom.: 440 Cov.: 32 AF XY: 0.0647 AC XY: 4815 AN XY: 74440

African (AFR) AF: 0.0140 AC: 583 AN: 41558

American (AMR) AF: 0.0968 AC: 1481 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0866 AC: 300 AN: 3466

East Asian (EAS) AF: 0.151 AC: 777 AN: 5150

South Asian (SAS) AF: 0.114 AC: 549 AN: 4818

European-Finnish (FIN) AF: 0.0727 AC: 772 AN: 10622

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.0715 AC: 4859 AN: 67998

Other (OTH) AF: 0.0639 AC: 135 AN: 2114

Alfa AF: 0.0696 Hom.: 296

Bravo AF: 0.0650

TwinsUK AF: 0.0698 AC: 259

ALSPAC AF: 0.0739 AC: 285

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.0737 AC: 634

ExAC AF: 0.0873 AC: 10602

Asia WGS AF: 0.117 AC: 408 AN: 3478

EpiCase AF: 0.0728

EpiControl AF: 0.0718

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.44
DANN	Benign	0.55
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-1.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.0030
Sift	Benign	0.26	T
Sift4G	Benign	0.16	T
Polyphen		0.028	B
Vest4		0.044
MPC		0.048
ClinPred		0.0018	T
GERP RS		-5.4
PromoterAI		0.0024	Neutral
Varity_R		0.044
gMVP		0.15
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs67346047; hg19: chr10-118957027; COSMIC: COSV57971204; COSMIC: COSV57971204;