8-139618677-C-T

Position:

• chr8-139618677-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001282534.2(KCNK9):​c.706G>A​(p.Gly236Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNK9 NM_001282534.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.83

Genes affected

KCNK9 (HGNC:6283): (potassium two pore domain channel subfamily K member 9) This gene encodes a protein that contains multiple transmembrane regions and two pore-forming P domains and functions as a pH-dependent potassium channel. Amplification and overexpression of this gene have been observed in several types of human carcinomas. This gene is imprinted in the brain, with preferential expression from the maternal allele. A mutation in this gene was associated with Birk-Barel dysmorphism syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNK9. . Gene score misZ 2.9038 (greater than the threshold 3.09). Trascript score misZ 3.4593 (greater than threshold 3.09). GenCC has associacion of gene with Birk-Barel syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 8-139618677-C-T is Pathogenic according to our data. Variant chr8-139618677-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNK9	NM_001282534.2	c.706G>A	p.Gly236Arg	missense_variant	2/2	ENST00000520439.3	NP_001269463.1
KCNK9	NR_104210.2	n.837G>A		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK9	ENST00000520439.3	c.706G>A	p.Gly236Arg	missense_variant	2/2	1	NM_001282534.2	ENSP00000430676	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birk-Barel syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.706G>A;p.(Gly236Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 465213; PMID: 18678320; 23236211; 27151206; 28882594; 30690205) - PS4.Same amino acid change as a previously established Pathogenic variant regardless of nucleotide change (c.706G>C; p.(Gly236Arg); PMID: 28333430; ClinVar ID:397636; GeneReviews: NBK425128) - PS1. This variant is not present in population databases:rs121908332, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is Pathogenic -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Dec 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 07, 2020	The KCNK9 c.706G>A (p.Gly236Arg) variant is a missense variant that has been reported in a heterozygous state in two studies (Barel et al. 2008; Graham et al. 2016). The variant was reported in a de novo state in two unrelated individuals with KCKN9 imprinting syndrome in Graham et al. (2016), and in at least 11 affected individuals showing segregation analysis in a large Israeli Arab family consistent with autosomal dominant inheritance with paternal imprinting (Barel et al. 2008). Additionally, de novo inheritance was noted in two unrelated affected individuals that carried a different nucleotide change resulting in the same amino acid consequence, c.706G>C (p.Gly236Arg). The p.Gly236Arg variant is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is a rare variant. Functional studies in mice expressing the mutant showed significantly higher calcium transients as compared to controls (Bando et al. 2014). Based on the collective evidence and application of the ACMG criteria, the p.Gly236Arg variant is classified as pathogenic for KCKN9 imprinting syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 07, 2021	0104 - Dominant negative is a known mechanism of disease in this gene and is associated with Birk-Barel syndrome (MIM#612292). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0113 - This gene is known to be imprinted. KCNK9 is expressed from the maternal allele (imprinted with paternal silencing) (PMID: 27151206). In this individual, this variant is located on the maternal allele. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial variability in terms of intellectual disability has been described in a large kindred (PMID: 18678320). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been found de novo in at least four patients and proven to segregate in a large Isreali Arab kindred (PMID: 18678320, 27151206). Diagnostic laboratories in Clinvar have classified this variant to be pathogenic (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 12, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2021	Published functional studies indicate that G236R results in a reduction of current suggestive of a dominant-negative effect (Barel et al., 2008; Veale et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18678320, 24342771, 27378938, 27151206, 30577886, 23236211) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;D;D;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;.;.;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.1	M;M;M;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.0	.;D;D;.;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.022	.;D;D;.;.
Sift4G	Uncertain	0.025	.;D;D;.;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.97, 0.96
MutPred		0.92		Gain of methylation at G236 (P = 0.0193);Gain of methylation at G236 (P = 0.0193);Gain of methylation at G236 (P = 0.0193);Gain of methylation at G236 (P = 0.0193);.;
MVP		0.81
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.88
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908332; hg19: chr8-140630920; COSMIC: COSV57283374; COSMIC: COSV57283374;