chr21-37911995-G-A

Variant names:

• chr21-37911995-G-A
• rs2836048
• NM_002240.5:c.-28+3889C>T

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+3889C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 151,958 control chromosomes in the GnomAD database, including 16,038 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 0.41 (16038 hom., cov: 32)
• Consequence: KCNJ6 NM_002240.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.169
• Publications: 6 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.-28+3889C>T		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+3889C>T		intron_variant	Intron 1 of 3	1	NM_002240.5	ENSP00000477437.1
KCNJ6	ENST00000645093.1	c.-27-71286C>T		intron_variant	Intron 2 of 4			ENSP00000493772.1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61691 AN: 151840 Hom.: 15992 Cov.: 32

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.362

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

GnomAD4 genome AF: 0.407 AC: 61791 AN: 151958 Hom.: 16038 Cov.: 32 AF XY: 0.406 AC XY: 30174 AN XY: 74256

African (AFR) AF: 0.719 AC: 29824 AN: 41468

American (AMR) AF: 0.385 AC: 5876 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 769 AN: 3462

East Asian (EAS) AF: 0.703 AC: 3639 AN: 5176

South Asian (SAS) AF: 0.427 AC: 2056 AN: 4814

European-Finnish (FIN) AF: 0.227 AC: 2393 AN: 10534

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16166 AN: 67914

Other (OTH) AF: 0.360 AC: 758 AN: 2106

Alfa AF: 0.296 Hom.: 23575

Bravo AF: 0.434

Asia WGS AF: 0.551 AC: 1908 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.45
PhyloP100		0.17
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: rs2836048; hg19: chr21-39284298;