chr8-139618451-G-A

Variant names:

• chr8-139618451-G-A
• rs767838359
• NM_001282534.2:c.932C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_001282534.2(KCNK9):​c.932C>T​(p.Ser311Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KCNK9 NM_001282534.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.675

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04215172).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK9	NM_001282534.2	c.932C>T	p.Ser311Leu	missense_variant	Exon 2 of 2	ENST00000520439.3	NP_001269463.1
KCNK9	NR_104210.2	n.1063C>T		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK9	ENST00000520439.3	c.932C>T	p.Ser311Leu	missense_variant	Exon 2 of 2	1	NM_001282534.2	ENSP00000430676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250740 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461630 Hom.: 0 Cov.: 29 AF XY: 0.00000550 AC XY: 4 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.2
DANN	Benign	0.28
DEOGEN2	Benign	0.23	T;T;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.55	.;T;.;.;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.042	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N;N;N;N;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.81	.;N;N;.;.
REVEL	Benign	0.017
Sift	Benign	0.73	.;T;T;.;.
Sift4G	Benign	0.67	.;T;T;.;.
Polyphen		0.0	B;B;B;B;.
Vest4		0.12, 0.073
MutPred		0.37		Loss of disorder (P = 0.0139);Loss of disorder (P = 0.0139);Loss of disorder (P = 0.0139);Loss of disorder (P = 0.0139);.;
MVP		0.32
MPC		0.97
ClinPred		0.023	T
GERP RS		1.0
Varity_R		0.032
gMVP		0.34

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: rs767838359; hg19: chr8-140630694; COSMIC: COSV57288374; COSMIC: COSV57288374;