21-37912532-C-T

Variant names:

• chr21-37912532-C-T
• rs2836050
• NM_002240.5:c.-28+3352G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002240.5(KCNJ6):​c.-28+3352G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 152,108 control chromosomes in the GnomAD database, including 10,574 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (10574 hom., cov: 33)
• Consequence: KCNJ6 NM_002240.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.404
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Keppen-Lubinsky syndrome

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.-28+3352G>A		intron_variant	Intron 1 of 3	ENST00000609713.2	NP_002231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ6	ENST00000609713.2	c.-28+3352G>A		intron_variant	Intron 1 of 3	1	NM_002240.5	ENSP00000477437.1
KCNJ6	ENST00000645093.1	c.-27-71823G>A		intron_variant	Intron 2 of 4			ENSP00000493772.1

Frequencies

GnomAD3 genomes AF: 0.322 AC: 49011 AN: 151988 Hom.: 10538 Cov.: 33

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.281

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.323 AC: 49101 AN: 152108 Hom.: 10574 Cov.: 33 AF XY: 0.320 AC XY: 23782 AN XY: 74348

African (AFR) AF: 0.613 AC: 25421 AN: 41492

American (AMR) AF: 0.235 AC: 3589 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 649 AN: 3470

East Asian (EAS) AF: 0.380 AC: 1970 AN: 5180

South Asian (SAS) AF: 0.358 AC: 1725 AN: 4814

European-Finnish (FIN) AF: 0.159 AC: 1684 AN: 10572

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13255 AN: 67976

Other (OTH) AF: 0.281 AC: 592 AN: 2108

Alfa AF: 0.179 Hom.: 571

Bravo AF: 0.340

Asia WGS AF: 0.380 AC: 1320 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.56
PhyloP100		-0.40
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: rs2836050; hg19: chr21-39284835;