rs702859

chr21-37625399-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002240.5(KCNJ6):c.1032C>T(p.Asp344=) 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:3
• Conservation: PhyloP100: -0.344

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
KCNJ6	NM_002240.5	c.1032C>T	p.Asp344=	synonymous_variant	4/4	ENST00000609713.2
KCNJ6-AS1	NR_183540.1	n.408-73156G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ6	ENST00000609713.2	c.1032C>T	p.Asp344=	synonymous_variant	4/4	1	NM_002240.5	P1
	ENST00000667151.1	n.161-21148G>A		intron_variant, non_coding_transcript_variant
KCNJ6	ENST00000645093.1	c.1032C>T	p.Asp344=	synonymous_variant	5/5			P1

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

GnomAD3 exomes AF: 0.711 AC: 177216 AN: 249130 Hom.: 63716 AF XY: 0.702 AC XY: 94910 AN XY: 135204

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 SAS exome AF: 0.655

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

Gnomad4 AFR exome AF: 0.806

Gnomad4 AMR exome AF: 0.798

Gnomad4 ASJ exome AF: 0.692

Gnomad4 EAS exome AF: 0.888

Gnomad4 SAS exome AF: 0.650

Gnomad4 FIN exome AF: 0.633

Gnomad4 NFE exome AF: 0.671

Gnomad4 OTH exome AF: 0.694

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

Gnomad4 AFR AF: 0.801

Gnomad4 AMR AF: 0.775

Gnomad4 ASJ AF: 0.698

Gnomad4 EAS AF: 0.870

Gnomad4 SAS AF: 0.662

Gnomad4 FIN AF: 0.634

Gnomad4 NFE AF: 0.680

Gnomad4 OTH AF: 0.722

Alfa AF: 0.691 Hom.: 32358

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Keppen-Lubinsky syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.65
Dann	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs702859; hg19: chr21-38997701;