11-64293042-C-T

Variant names:

• chr11-64293042-C-T
• rs76192175
• NM_033310.3:c.24C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_033310.3(KCNK4):​c.24C>T​(p.Ala8Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00637 in 1,547,802 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (46 hom.)
• Consequence: KCNK4 NM_033310.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -6.10
• Publications: 2 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 11-64293042-C-T is Benign according to our data. Variant chr11-64293042-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1575952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.1 with no splicing effect.
• BS2: High AC in GnomAd4 at 594 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.24C>T	p.Ala8Ala	synonymous	Exon 2 of 7	NP_201567.1	Q9NYG8-1
	KCNK4	NM_001317090.2		c.24C>T	p.Ala8Ala	synonymous	Exon 2 of 7	NP_001304019.1	Q9NYG8-1
	KCNK4	NR_133661.2		n.164C>T		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.24C>T	p.Ala8Ala	synonymous	Exon 2 of 7	ENSP00000402797.2	Q9NYG8-1
	KCNK4	ENST00000394525.6	TSL:1	c.24C>T	p.Ala8Ala	synonymous	Exon 2 of 7	ENSP00000378033.2	Q9NYG8-1
	KCNK4	ENST00000539216.1	TSL:1	c.24C>T	p.Ala8Ala	synonymous	Exon 1 of 6	ENSP00000444948.1	Q9NYG8-1

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 594 AN: 152246 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00345 AC: 522 AN: 151356 AF XY: 0.00349

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.00356

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00234

GnomAD4 exome AF: 0.00664 AC: 9260 AN: 1395438 Hom.: 46 Cov.: 31 AF XY: 0.00636 AC XY: 4377 AN XY: 688208

African (AFR) AF: 0.000827 AC: 26 AN: 31448

American (AMR) AF: 0.00189 AC: 67 AN: 35450

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 72 AN: 25100

East Asian (EAS) AF: 0.00 AC: 0 AN: 35582

South Asian (SAS) AF: 0.000939 AC: 74 AN: 78792

European-Finnish (FIN) AF: 0.00177 AC: 85 AN: 48108

Middle Eastern (MID) AF: 0.000967 AC: 5 AN: 5170

European-Non Finnish (NFE) AF: 0.00797 AC: 8592 AN: 1077978

Other (OTH) AF: 0.00586 AC: 339 AN: 57810

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152364 Hom.: 3 Cov.: 33 AF XY: 0.00352 AC XY: 262 AN XY: 74510

African (AFR) AF: 0.00137 AC: 57 AN: 41582

American (AMR) AF: 0.00307 AC: 47 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10632

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00660 AC: 449 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00512 Hom.: 1

Bravo AF: 0.00386

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	KCNK4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.0
DANN	Benign	0.94
PhyloP100		-6.1
PromoterAI		-0.033	Neutral
Mutation Taster		=100/0	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: rs76192175; hg19: chr11-64060514;