NM_002240.5:c.26-32697C>G

Variant names:

• chr21-37747828-G-C
• rs857989
• NM_002240.5:c.26-32697C>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.26-32697C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 152,238 control chromosomes in the GnomAD database, including 1,779 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 0.14 (1779 hom., cov: 32)
• Consequence: KCNJ6 NM_002240.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.465
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.26-32697C>G		intron_variant	Intron 2 of 3	ENST00000609713.2	NP_002231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ6	ENST00000609713.2	c.26-32697C>G		intron_variant	Intron 2 of 3	1	NM_002240.5	ENSP00000477437.1
KCNJ6	ENST00000645093.1	c.26-32697C>G		intron_variant	Intron 3 of 4			ENSP00000493772.1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22033 AN: 152120 Hom.: 1777 Cov.: 32

Gnomad AFR AF: 0.0968

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.146

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

GnomAD4 genome AF: 0.145 AC: 22043 AN: 152238 Hom.: 1779 Cov.: 32 AF XY: 0.147 AC XY: 10977 AN XY: 74432

African (AFR) AF: 0.0967 AC: 4018 AN: 41550

American (AMR) AF: 0.196 AC: 2999 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 510 AN: 3470

East Asian (EAS) AF: 0.0497 AC: 257 AN: 5174

South Asian (SAS) AF: 0.157 AC: 756 AN: 4824

European-Finnish (FIN) AF: 0.196 AC: 2078 AN: 10598

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10904 AN: 67996

Other (OTH) AF: 0.147 AC: 310 AN: 2116

Alfa AF: 0.156 Hom.: 254

Bravo AF: 0.142

Asia WGS AF: 0.130 AC: 450 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.5
DANN	Benign	0.68
PhyloP100		0.47
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: rs857989; hg19: chr21-39120131;