rs786204795

Positions:

• chr21-37714697-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_002240.5(KCNJ6):​c.460G>A​(p.Gly154Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ6 NM_002240.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91

Genes affected

KCNJ6 (HGNC:6267): (potassium inwardly rectifying channel subfamily J member 6) This gene encodes a member of the G protein-coupled inwardly-rectifying potassium channel family of inward rectifier potassium channels. This type of potassium channel allows a greater flow of potassium into the cell than out of it. These proteins modulate many physiological processes, including heart rate in cardiac cells and circuit activity in neuronal cells, through G-protein coupled receptor stimulation. Mutations in this gene are associated with Keppen-Lubinsky Syndrome, a rare condition characterized by severe developmental delay, facial dysmorphism, and intellectual disability. [provided by RefSeq, Apr 2015]

KCNJ6-AS1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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), KCNJ6. . Gene score misZ 3.7134 (greater than the threshold 3.09). Trascript score misZ 4.9887 (greater than threshold 3.09). GenCC has associacion of gene with Keppen-Lubinsky syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 21-37714697-C-T is Pathogenic according to our data. Variant chr21-37714697-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189255.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-37714697-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ6	NM_002240.5	c.460G>A	p.Gly154Ser	missense_variant	3/4	ENST00000609713.2
KCNJ6-AS1	NR_183540.1	n.1139C>T		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ6	ENST00000609713.2	c.460G>A	p.Gly154Ser	missense_variant	3/4	1	NM_002240.5	P1
KCNJ6-AS1	ENST00000711629.1	n.732C>T		non_coding_transcript_exon_variant	3/7
KCNJ6	ENST00000645093.1	c.460G>A	p.Gly154Ser	missense_variant	4/5			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Keppen-Lubinsky syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 05, 2015

- -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.2	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.97		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.88
MPC		2.3
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.90
gMVP		1.0

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: rs786204795; hg19: chr21-39087000;