chr21-37625824-A-G

Variant names:

• chr21-37625824-A-G
• rs857978
• NM_002240.5:c.947-340T>C

Variant summary

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

The NM_002240.5(KCNJ6):​c.947-340T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 152,260 control chromosomes in the GnomAD database, including 37,894 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 0.70 (37894 hom., cov: 35)
• Consequence: KCNJ6 NM_002240.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0140
• Publications: 3 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]

ENSG00000286717 (HGNC:):

KCNJ6-AS1 (HGNC:41352): (KCNJ6 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002240.5. 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
	KCNJ6	NM_002240.5	MANE Select	c.947-340T>C		intron	N/A	NP_002231.1
	KCNJ6-AS1	NR_183540.1		n.408-72731A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ6	ENST00000609713.2	TSL:1 MANE Select	c.947-340T>C		intron	N/A	ENSP00000477437.1
	KCNJ6	ENST00000645093.1		c.947-340T>C		intron	N/A	ENSP00000493772.1
	ENSG00000286717	ENST00000667151.1		n.161-20723A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.703 AC: 107014 AN: 152142 Hom.: 37871 Cov.: 35

Gnomad AFR AF: 0.744

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.699

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

GnomAD4 genome AF: 0.703 AC: 107080 AN: 152260 Hom.: 37894 Cov.: 35 AF XY: 0.702 AC XY: 52274 AN XY: 74448

African (AFR) AF: 0.744 AC: 30932 AN: 41566

American (AMR) AF: 0.756 AC: 11568 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2361 AN: 3472

East Asian (EAS) AF: 0.802 AC: 4157 AN: 5182

South Asian (SAS) AF: 0.649 AC: 3128 AN: 4822

European-Finnish (FIN) AF: 0.634 AC: 6724 AN: 10602

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.678 AC: 46079 AN: 67996

Other (OTH) AF: 0.698 AC: 1476 AN: 2116

Alfa AF: 0.683 Hom.: 59503

Bravo AF: 0.713

Asia WGS AF: 0.752 AC: 2612 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.6
DANN	Benign	0.69
PhyloP100		0.014
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: rs857978; hg19: chr21-38998126;