chr8-139618327-G-C

Position:

• chr8-139618327-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001282534.2(KCNK9):​c.1056C>G​(p.Ser352Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNK9 NM_001282534.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.41

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 Uncertain_significance. Variant got 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41186467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNK9	NM_001282534.2	c.1056C>G	p.Ser352Arg	missense_variant	2/2	ENST00000520439.3	NP_001269463.1
KCNK9	NR_104210.2	n.1187C>G		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK9	ENST00000520439.3	c.1056C>G	p.Ser352Arg	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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

KCNK9: PM2, PP2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	0.0068	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D;D;D;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;D;.;.;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	.;D;D;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.0030	.;D;D;.;.
Sift4G	Uncertain	0.0050	.;D;D;.;.
Polyphen		0.99	D;D;D;D;.
Vest4		0.44, 0.39
MutPred		0.41		Loss of phosphorylation at S352 (P = 0.0296);Loss of phosphorylation at S352 (P = 0.0296);Loss of phosphorylation at S352 (P = 0.0296);Loss of phosphorylation at S352 (P = 0.0296);.;
MVP		0.80
MPC		2.3
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.63
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-140630570;