chr21-37916461-T-C

Variant names:

• chr21-37916461-T-C
• rs11702683
• ENST00000645093.1:c.-27-75752A>G

Variant summary

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

The ENST00000645093.1(KCNJ6):​c.-27-75752A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 149,386 control chromosomes in the GnomAD database, including 40,399 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 0.73 (40379 hom., cov: 27)
  • Exomes 𝑓: 0.51 (20 hom.)
• Consequence: KCNJ6 ENST00000645093.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 4 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=-0.57).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000645093.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ6	NM_002240.5	MANE Select	c.-605A>G		upstream_gene	N/A	NP_002231.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ6	ENST00000645093.1		c.-27-75752A>G		intron	N/A	ENSP00000493772.1
	KCNJ6	ENST00000609713.2	TSL:1 MANE Select	c.-605A>G		upstream_gene	N/A	ENSP00000477437.1
	KCNJ6	ENST00000917423.1		c.-1191A>G		upstream_gene	N/A	ENSP00000587482.1

Frequencies

GnomAD3 genomes AF: 0.726 AC: 108340 AN: 149128 Hom.: 40325 Cov.: 27

Gnomad AFR AF: 0.903

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.747

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.918

Gnomad SAS AF: 0.809

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.619

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.710

GnomAD4 exome AF: 0.507 AC: 69 AN: 136 Hom.: 20 Cov.: 0 AF XY: 0.451 AC XY: 37 AN XY: 82

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.508 AC: 65 AN: 128

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.727 AC: 108456 AN: 149250 Hom.: 40379 Cov.: 27 AF XY: 0.730 AC XY: 53086 AN XY: 72686

African (AFR) AF: 0.903 AC: 37117 AN: 41082

American (AMR) AF: 0.747 AC: 11153 AN: 14922

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 2254 AN: 3416

East Asian (EAS) AF: 0.918 AC: 4629 AN: 5042

South Asian (SAS) AF: 0.808 AC: 3765 AN: 4660

European-Finnish (FIN) AF: 0.650 AC: 6578 AN: 10122

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.611 AC: 40775 AN: 66744

Other (OTH) AF: 0.713 AC: 1471 AN: 2062

Alfa AF: 0.595 Hom.: 3824

Bravo AF: 0.734

Asia WGS AF: 0.837 AC: 2910 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.73
PhyloP100		1.7
PromoterAI		-0.019	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11702683; hg19: chr21-39288764;