rs702859

Variant names:

• chr21-37625399-G-A
• rs702859
• NM_002240.5:c.1032C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002240.5(KCNJ6):​c.1032C>T​(p.Asp344Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,613,624 control chromosomes in the GnomAD database, including 382,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40429 hom., cov: 32)
  • Exomes 𝑓: 0.68 (341960 hom.)
• Consequence: KCNJ6 NM_002240.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.344
• Publications: 33 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]

ENSG00000286717 (HGNC:):

KCNJ6-AS1 (HGNC:41352): (KCNJ6 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 21-37625399-G-A is Benign according to our data. Variant chr21-37625399-G-A is described in ClinVar as Benign. ClinVar VariationId is 1170806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.344 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.1032C>T	p.Asp344Asp	synonymous_variant	Exon 4 of 4	ENST00000609713.2	NP_002231.1
KCNJ6-AS1	NR_183540.1	n.408-73156G>A		intron_variant	Intron 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ6	ENST00000609713.2	c.1032C>T	p.Asp344Asp	synonymous_variant	Exon 4 of 4	1	NM_002240.5	ENSP00000477437.1
KCNJ6	ENST00000645093.1	c.1032C>T	p.Asp344Asp	synonymous_variant	Exon 5 of 5			ENSP00000493772.1
ENSG00000286717	ENST00000667151.1	n.161-21148G>A		intron_variant	Intron 1 of 2
ENSG00000286717	ENST00000838658.1	n.234+31263G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110211 AN: 152004 Hom.: 40392 Cov.: 32

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.719

GnomAD2 exomes AF: 0.711 AC: 177216 AN: 249130 AF XY: 0.702

Gnomad AFR exome AF: 0.800

Gnomad AMR exome AF: 0.799

Gnomad ASJ exome AF: 0.695

Gnomad EAS exome AF: 0.870

Gnomad FIN exome AF: 0.633

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.691

GnomAD4 exome AF: 0.682 AC: 996864 AN: 1461502 Hom.: 341960 Cov.: 47 AF XY: 0.681 AC XY: 495089 AN XY: 727094

African (AFR) AF: 0.806 AC: 26963 AN: 33470

American (AMR) AF: 0.798 AC: 35697 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 18091 AN: 26130

East Asian (EAS) AF: 0.888 AC: 35242 AN: 39698

South Asian (SAS) AF: 0.650 AC: 56023 AN: 86252

European-Finnish (FIN) AF: 0.633 AC: 33803 AN: 53420

Middle Eastern (MID) AF: 0.646 AC: 3724 AN: 5768

European-Non Finnish (NFE) AF: 0.671 AC: 745440 AN: 1111652

Other (OTH) AF: 0.694 AC: 41881 AN: 60390

GnomAD4 genome AF: 0.725 AC: 110299 AN: 152122 Hom.: 40429 Cov.: 32 AF XY: 0.723 AC XY: 53762 AN XY: 74354

African (AFR) AF: 0.801 AC: 33263 AN: 41520

American (AMR) AF: 0.775 AC: 11855 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 2421 AN: 3470

East Asian (EAS) AF: 0.870 AC: 4488 AN: 5160

South Asian (SAS) AF: 0.662 AC: 3191 AN: 4820

European-Finnish (FIN) AF: 0.634 AC: 6702 AN: 10570

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.680 AC: 46201 AN: 67972

Other (OTH) AF: 0.722 AC: 1524 AN: 2110

Alfa AF: 0.699 Hom.: 85252

Bravo AF: 0.738

Asia WGS AF: 0.810 AC: 2813 AN: 3478

EpiCase AF: 0.680

EpiControl AF: 0.670

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Keppen-Lubinsky syndrome Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.65
DANN	Benign	0.49
PhyloP100		-0.34
Mutation Taster		=92/8	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: rs702859; hg19: chr21-38997701; COSMIC: COSV108050505;