21-37897149-C-T

Variant names:

• chr21-37897149-C-T
• rs933127
• NM_002240.5:c.-28+18735G>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+18735G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,194 control chromosomes in the GnomAD database, including 2,896 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 0.19 (2896 hom., cov: 32)
• Consequence: KCNJ6 NM_002240.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0350
• Publications: 1 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 (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.-28+18735G>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+18735G>A		intron_variant	Intron 1 of 3	1	NM_002240.5	ENSP00000477437.1
KCNJ6	ENST00000645093.1	c.-27-56440G>A		intron_variant	Intron 2 of 4			ENSP00000493772.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28239 AN: 152076 Hom.: 2889 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.157

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

GnomAD4 genome AF: 0.186 AC: 28270 AN: 152194 Hom.: 2896 Cov.: 32 AF XY: 0.187 AC XY: 13893 AN XY: 74412

African (AFR) AF: 0.233 AC: 9687 AN: 41524

American (AMR) AF: 0.178 AC: 2720 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3472

East Asian (EAS) AF: 0.318 AC: 1638 AN: 5152

South Asian (SAS) AF: 0.241 AC: 1164 AN: 4822

European-Finnish (FIN) AF: 0.151 AC: 1598 AN: 10608

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10665 AN: 67992

Other (OTH) AF: 0.156 AC: 329 AN: 2114

Alfa AF: 0.152 Hom.: 1124

Bravo AF: 0.190

Asia WGS AF: 0.261 AC: 907 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	1.7
DANN	Benign	0.19
PhyloP100		-0.035
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: rs933127; hg19: chr21-39269452;