21-37833852-A-C

Variant names:

• chr21-37833852-A-C
• rs991985
• NM_002240.5:c.25+6806T>G

Variant summary

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

The NM_002240.5(KCNJ6):​c.25+6806T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.746 in 152,148 control chromosomes in the GnomAD database, including 43,305 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 0.75 (43305 hom., cov: 32)
• Consequence: KCNJ6 NM_002240.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.670
• Publications: 7 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)

ENSG00000289538 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.95 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.25+6806T>G		intron	N/A	NP_002231.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ6	ENST00000609713.2	TSL:1 MANE Select	c.25+6806T>G		intron	N/A	ENSP00000477437.1
	KCNJ6	ENST00000645093.1		c.25+6806T>G		intron	N/A	ENSP00000493772.1
	ENSG00000289538	ENST00000692486.3		n.202-6576A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113387 AN: 152030 Hom.: 43250 Cov.: 32

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.885

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.747

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

GnomAD4 genome AF: 0.746 AC: 113501 AN: 152148 Hom.: 43305 Cov.: 32 AF XY: 0.749 AC XY: 55704 AN XY: 74350

African (AFR) AF: 0.883 AC: 36662 AN: 41518

American (AMR) AF: 0.772 AC: 11822 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2560 AN: 3470

East Asian (EAS) AF: 0.973 AC: 5033 AN: 5174

South Asian (SAS) AF: 0.885 AC: 4266 AN: 4822

European-Finnish (FIN) AF: 0.644 AC: 6801 AN: 10560

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.645 AC: 43852 AN: 67980

Other (OTH) AF: 0.749 AC: 1584 AN: 2114

Alfa AF: 0.705 Hom.: 32307

Bravo AF: 0.760

Asia WGS AF: 0.921 AC: 3198 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	7.3
DANN	Benign	0.51
PhyloP100		0.67
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: rs991985; hg19: chr21-39206154;