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
• Publications: 21 publications found

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]

KCNK9 Gene-Disease associations (from GenCC):

• Birk-Barel syndrome

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina

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 VariationId is 1174840.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282534.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK9	NM_001282534.2	MANE Select	c.636T>C	p.Gly212Gly	synonymous	Exon 2 of 2	NP_001269463.1
	KCNK9	NR_104210.2		n.767T>C		non_coding_transcript_exon	Exon 2 of 4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK9	ENST00000520439.3	TSL:1 MANE Select	c.636T>C	p.Gly212Gly	synonymous	Exon 2 of 2	ENSP00000430676.1
	KCNK9	ENST00000303015.2	TSL:1	c.636T>C	p.Gly212Gly	synonymous	Exon 2 of 3	ENSP00000302166.1
	KCNK9	ENST00000648164.1		c.636T>C	p.Gly212Gly	synonymous	Exon 2 of 2	ENSP00000498198.1

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

African (AFR) AF: 0.857 AC: 28697 AN: 33480

American (AMR) AF: 0.692 AC: 30940 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 14635 AN: 26136

East Asian (EAS) AF: 0.702 AC: 27864 AN: 39698

South Asian (SAS) AF: 0.618 AC: 53337 AN: 86254

European-Finnish (FIN) AF: 0.643 AC: 34364 AN: 53416

Middle Eastern (MID) AF: 0.623 AC: 3593 AN: 5768

European-Non Finnish (NFE) AF: 0.637 AC: 708114 AN: 1111998

Other (OTH) 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

African (AFR) AF: 0.848 AC: 35217 AN: 41510

American (AMR) AF: 0.675 AC: 10319 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 1927 AN: 3470

East Asian (EAS) AF: 0.690 AC: 3551 AN: 5144

South Asian (SAS) AF: 0.627 AC: 3016 AN: 4810

European-Finnish (FIN) AF: 0.641 AC: 6776 AN: 10568

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.630 AC: 42784 AN: 67962

Other (OTH) AF: 0.693 AC: 1461 AN: 2108

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.3
DANN	Benign	0.38
PhyloP100		-0.89
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

Other links and lift over

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