NM_033310.3:c.93C>G

Variant names:

• chr11-64293111-C-G
• rs202162247
• NM_033310.3:c.93C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_033310.3(KCNK4):​c.93C>G​(p.His31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,395,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: KCNK4 NM_033310.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.58
• Publications: 5 publications found

Genes affected

KCNK4 (HGNC:6279): (potassium two pore domain channel subfamily K member 4) This gene encodes a member of the TWIK-related arachidonic acid-stimulated two pore potassium channel subfamily. The encoded protein homodimerizes and functions as an outwardly rectifying channel. This channel is regulated by polyunsaturated fatty acids, temperature and mechanical deformation of the lipid membrane. This protein is expressed primarily in neural tissues and may be involved in regulating the noxious input threshold in dorsal root ganglia neurons. Alternate splicing results in multiple transcript variants. Naturally occurring read-through transcripts also exist between this gene and the downstream testis expressed 40 (TEX40) gene, as represented in GeneID: 106780802. [provided by RefSeq, Nov 2015]

KCNK4-CATSPERZ (HGNC:56753): (KCNK4-CATSPERZ readthrough (NMD candidate)) This locus represents naturally occurring readthrough transcription between the neighboring KCNK4 (potassium channel subfamily K member 4) and the downstream TEX40 (testis expressed 40) chromosome 11. The readthrough transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Nov 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030884475).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033310.3. 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
	KCNK4	NM_033310.3	MANE Select	c.93C>G	p.His31Gln	missense	Exon 2 of 7	NP_201567.1	Q9NYG8-1
	KCNK4	NM_001317090.2		c.93C>G	p.His31Gln	missense	Exon 2 of 7	NP_001304019.1	Q9NYG8-1
	KCNK4	NR_133661.2		n.233C>G		non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK4	ENST00000422670.7	TSL:1 MANE Select	c.93C>G	p.His31Gln	missense	Exon 2 of 7	ENSP00000402797.2	Q9NYG8-1
	KCNK4	ENST00000394525.6	TSL:1	c.93C>G	p.His31Gln	missense	Exon 2 of 7	ENSP00000378033.2	Q9NYG8-1
	KCNK4	ENST00000539216.1	TSL:1	c.93C>G	p.His31Gln	missense	Exon 1 of 6	ENSP00000444948.1	Q9NYG8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1395180 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688050

African (AFR) AF: 0.00 AC: 0 AN: 31442

American (AMR) AF: 0.00 AC: 0 AN: 35228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25052

East Asian (EAS) AF: 0.00 AC: 0 AN: 35480

South Asian (SAS) AF: 0.00 AC: 0 AN: 78502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1077320

Other (OTH) AF: 0.00 AC: 0 AN: 57838

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.3
DANN	Benign	0.86
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N
PhyloP100		-2.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.060
Sift	Benign	0.39	T
Sift4G	Benign	0.53	T
Polyphen		0.0080	B
Vest4		0.12
MutPred		0.28		Gain of relative solvent accessibility (P = 0.0999)
MVP		0.14
MPC		0.30
ClinPred		0.14	T
GERP RS		-5.5
PromoterAI		0.044	Neutral
Varity_R		0.25
gMVP		0.14
Mutation Taster		=71/29	polymorphism

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: rs202162247; hg19: chr11-64060583;