chr21-37916620-G-A

Variant names:

• chr21-37916620-G-A
• rs7276069
• ENST00000645093.1:c.-27-75911C>T

Variant summary

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

The ENST00000645093.1(KCNJ6):​c.-27-75911C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 151,972 control chromosomes in the GnomAD database, including 36,435 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 0.68 (36435 hom., cov: 32)
• Consequence: KCNJ6 ENST00000645093.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.241
• Publications: 2 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=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.-764C>T		upstream_gene_variant		ENST00000609713.2	NP_002231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ6	ENST00000645093.1	c.-27-75911C>T		intron_variant	Intron 2 of 4			ENSP00000493772.1
KCNJ6	ENST00000609713.2	c.-764C>T		upstream_gene_variant		1	NM_002240.5	ENSP00000477437.1

Frequencies

GnomAD3 genomes AF: 0.682 AC: 103595 AN: 151852 Hom.: 36402 Cov.: 32

Gnomad AFR AF: 0.855

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.741

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.666

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

GnomAD4 genome AF: 0.682 AC: 103685 AN: 151972 Hom.: 36435 Cov.: 32 AF XY: 0.682 AC XY: 50674 AN XY: 74260

African (AFR) AF: 0.854 AC: 35443 AN: 41494

American (AMR) AF: 0.691 AC: 10567 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 2122 AN: 3472

East Asian (EAS) AF: 0.693 AC: 3546 AN: 5120

South Asian (SAS) AF: 0.740 AC: 3568 AN: 4822

European-Finnish (FIN) AF: 0.609 AC: 6439 AN: 10566

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.587 AC: 39878 AN: 67896

Other (OTH) AF: 0.669 AC: 1412 AN: 2112

Alfa AF: 0.647 Hom.: 4910

Bravo AF: 0.697

Asia WGS AF: 0.705 AC: 2453 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.4
DANN	Benign	0.96
PhyloP100		-0.24
PromoterAI		0.034	Neutral

Splicing

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

Other links and lift over

dbSNP: rs7276069; hg19: chr21-39288923;