chr8-139618747-A-G

Variant names:

• chr8-139618747-A-G
• rs2615374
• NM_001282534.2:c.636T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001282534.2(KCNK9):​c.636T>C​(p.Gly212Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,613,930 control chromosomes in the GnomAD database, including 341,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.70 (37437 hom., cov: 32)
  • Exomes 𝑓: 0.64 (304330 hom.)
• Consequence: KCNK9 NM_001282534.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.891

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

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 8-139618747-A-G is Benign according to our data. Variant chr8-139618747-A-G is described in ClinVar as [Benign]. Clinvar id is 1174840.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-139618747-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.891 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK9	NM_001282534.2	c.636T>C	p.Gly212Gly	synonymous_variant	Exon 2 of 2	ENST00000520439.3	NP_001269463.1
KCNK9	NR_104210.2	n.767T>C		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.636T>C	p.Gly212Gly	synonymous_variant	Exon 2 of 2	1	NM_001282534.2	ENSP00000430676.1

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105579 AN: 151944 Hom.: 37385 Cov.: 32

Gnomad AFR AF: 0.848

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.641

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.630

Gnomad OTH AF: 0.692

GnomAD2 exomes AF: 0.656 AC: 164883 AN: 251280 AF XY: 0.646

Gnomad AFR exome AF: 0.854

Gnomad AMR exome AF: 0.695

Gnomad ASJ exome AF: 0.562

Gnomad EAS exome AF: 0.689

Gnomad FIN exome AF: 0.643

Gnomad NFE exome AF: 0.632

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.643 AC: 940567 AN: 1461868 Hom.: 304330 Cov.: 78 AF XY: 0.641 AC XY: 466296 AN XY: 727240

Gnomad4 AFR exome AF: 0.857 AC: 28697 AN: 33480

Gnomad4 AMR exome AF: 0.692 AC: 30940 AN: 44722

Gnomad4 ASJ exome AF: 0.560 AC: 14635 AN: 26136

Gnomad4 EAS exome AF: 0.702 AC: 27864 AN: 39698

Gnomad4 SAS exome AF: 0.618 AC: 53337 AN: 86254

Gnomad4 FIN exome AF: 0.643 AC: 34364 AN: 53416

Gnomad4 NFE exome AF: 0.637 AC: 708114 AN: 1111998

Gnomad4 Remaining exome AF: 0.646 AC: 39023 AN: 60396

GnomAD4 genome AF: 0.695 AC: 105688 AN: 152062 Hom.: 37437 Cov.: 32 AF XY: 0.692 AC XY: 51424 AN XY: 74314

Gnomad4 AFR AF: 0.848 AC: 0.848398 AN: 0.848398

Gnomad4 AMR AF: 0.675 AC: 0.67515 AN: 0.67515

Gnomad4 ASJ AF: 0.555 AC: 0.555331 AN: 0.555331

Gnomad4 EAS AF: 0.690 AC: 0.690319 AN: 0.690319

Gnomad4 SAS AF: 0.627 AC: 0.627027 AN: 0.627027

Gnomad4 FIN AF: 0.641 AC: 0.641181 AN: 0.641181

Gnomad4 NFE AF: 0.630 AC: 0.629528 AN: 0.629528

Gnomad4 OTH AF: 0.693 AC: 0.693074 AN: 0.693074

Alfa AF: 0.655 Hom.: 52931

Bravo AF: 0.707

Asia WGS AF: 0.695 AC: 2415 AN: 3478

EpiCase AF: 0.626

EpiControl AF: 0.624

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.3
DANN	Benign	0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs2615374; hg19: chr8-140630990; COSMIC: COSV57280146; COSMIC: COSV57280146;