rs2070995

Variant names:

• chr21-37714662-T-C
• rs2070995
• NM_002240.5:c.495A>G

Your query was ambiguous. Multiple possible variants found:

• chr21-37714662-T-C
• chr21-37714662-T-A
• chr21-37714662-T-G

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.495A>G​(p.Pro165Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.795 in 1,613,810 control chromosomes in the GnomAD database, including 512,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54328 hom., cov: 32)
  • Exomes 𝑓: 0.79 (458388 hom.)
• Consequence: KCNJ6 NM_002240.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.48
• Publications: 52 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-AS1 (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=-0.95).
• BP6: Variant 21-37714662-T-C is Benign according to our data. Variant chr21-37714662-T-C is described in ClinVar as Benign. ClinVar VariationId is 1165658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002240.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ6	NM_002240.5	MANE Select	c.495A>G	p.Pro165Pro	synonymous	Exon 3 of 4	NP_002231.1	P48051
	KCNJ6-AS1	NR_183540.1		n.1104T>C		non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ6	ENST00000609713.2	TSL:1 MANE Select	c.495A>G	p.Pro165Pro	synonymous	Exon 3 of 4	ENSP00000477437.1	P48051
	KCNJ6	ENST00000645093.1		c.495A>G	p.Pro165Pro	synonymous	Exon 4 of 5	ENSP00000493772.1	P48051
	KCNJ6	ENST00000917423.1		c.495A>G	p.Pro165Pro	synonymous	Exon 4 of 5	ENSP00000587482.1

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127862 AN: 152102 Hom.: 54271 Cov.: 32

Gnomad AFR AF: 0.959

Gnomad AMI AF: 0.822

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.841

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.828

Gnomad NFE AF: 0.791

Gnomad OTH AF: 0.819

GnomAD2 exomes AF: 0.803 AC: 200271 AN: 249408 AF XY: 0.801

Gnomad AFR exome AF: 0.965

Gnomad AMR exome AF: 0.804

Gnomad ASJ exome AF: 0.824

Gnomad EAS exome AF: 0.616

Gnomad FIN exome AF: 0.853

Gnomad NFE exome AF: 0.792

Gnomad OTH exome AF: 0.796

GnomAD4 exome AF: 0.790 AC: 1155105 AN: 1461590 Hom.: 458388 Cov.: 49 AF XY: 0.791 AC XY: 574862 AN XY: 727098

African (AFR) AF: 0.969 AC: 32428 AN: 33478

American (AMR) AF: 0.806 AC: 36047 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 21507 AN: 26136

East Asian (EAS) AF: 0.627 AC: 24911 AN: 39700

South Asian (SAS) AF: 0.829 AC: 71509 AN: 86244

European-Finnish (FIN) AF: 0.853 AC: 45515 AN: 53358

Middle Eastern (MID) AF: 0.847 AC: 4884 AN: 5768

European-Non Finnish (NFE) AF: 0.783 AC: 870511 AN: 1111804

Other (OTH) AF: 0.791 AC: 47793 AN: 60384

GnomAD4 genome AF: 0.841 AC: 127980 AN: 152220 Hom.: 54328 Cov.: 32 AF XY: 0.843 AC XY: 62739 AN XY: 74410

African (AFR) AF: 0.959 AC: 39826 AN: 41544

American (AMR) AF: 0.817 AC: 12504 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 2865 AN: 3472

East Asian (EAS) AF: 0.620 AC: 3203 AN: 5168

South Asian (SAS) AF: 0.842 AC: 4048 AN: 4810

European-Finnish (FIN) AF: 0.854 AC: 9056 AN: 10600

Middle Eastern (MID) AF: 0.825 AC: 241 AN: 292

European-Non Finnish (NFE) AF: 0.791 AC: 53763 AN: 68004

Other (OTH) AF: 0.816 AC: 1724 AN: 2114

Alfa AF: 0.805 Hom.: 139729

Bravo AF: 0.837

Asia WGS AF: 0.762 AC: 2650 AN: 3478

EpiCase AF: 0.790

EpiControl AF: 0.790

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Keppen-Lubinsky syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.16
DANN	Benign	0.57
PhyloP100		-3.5
Mutation Taster		=99/1	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: rs2070995; hg19: chr21-39086965; COSMIC: COSV55709196; COSMIC: COSV55709196;