8-139618991-C-T

Variant names:

• chr8-139618991-C-T
• rs867543866
• NM_001282534.2:c.392G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_001282534.2(KCNK9):​c.392G>A​(p.Arg131His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R131C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNK9 NM_001282534.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.00
• Publications: 4 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: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-139618992-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 983124.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82
• PP5: Variant 8-139618991-C-T is Pathogenic according to our data. Variant chr8-139618991-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 372887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK9	NM_001282534.2	c.392G>A	p.Arg131His	missense_variant	Exon 2 of 2	ENST00000520439.3	NP_001269463.1
KCNK9	NR_104210.2	n.523G>A		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.392G>A	p.Arg131His	missense_variant	Exon 2 of 2	1	NM_001282534.2	ENSP00000430676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birk-Barel syndrome Pathogenic:4

Jul 01, 2021

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 17, 2021

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNK9 c.392G>A (p.Arg131His) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. However, multiple clinical laboratories in ClinVar have provided a likely pathogenic classification for this variant, which was noted to have occurred de novo in a male patient who was tested by the Baylor Genetics laboratory, and whose information was presumably published (Yang et al. 2014). This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequence coverage, which suggests the variant is rare. Multiple lines of computational evidence suggest that this variant will have a deleterious impact on the protein. This variant was identified in a de novo state. Based on the available evidence, the p.Arg131His variant is classified as likely pathogenic for KCNK9-imprinting syndrome, also known as Birk-Barel syndrome. -

Jan 25, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Oct 22, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R131H variant in the KCNK9 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R131H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R131H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R131H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Inborn genetic diseases Pathogenic:1

Dec 07, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;D;D;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	.;D;.;.;D
M_CAP	Benign	0.0083	T
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.1	M;M;M;M;.
PhyloP100		6.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	.;D;D;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	.;D;D;.;.
Sift4G	Uncertain	0.0030	.;D;D;.;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.80, 0.77
MutPred		0.67		Loss of MoRF binding (P = 0.0364);Loss of MoRF binding (P = 0.0364);Loss of MoRF binding (P = 0.0364);Loss of MoRF binding (P = 0.0364);.;
MVP		0.83
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.74
gMVP		0.93
Mutation Taster		=48/52	disease causing (ClinVar)

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: rs867543866; hg19: chr8-140631234; COSMIC: COSV105881829; COSMIC: COSV105881829;