rs80246222

Variant names:

• chr1-215195099-A-C
• rs80246222
• NM_001017425.3:c.963+7A>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001017425.3(KCNK2):​c.963+7A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,586,958 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (12 hom.)
• Consequence: KCNK2 NM_001017425.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002276
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.445
• Publications: 1 publications found

Genes affected

KCNK2 (HGNC:6277): (potassium two pore domain channel subfamily K member 2) This gene encodes one of the members of the two-pore-domain background potassium channel protein family. This type of potassium channel is formed by two homodimers that create a channel that leaks potassium out of the cell to control resting membrane potential. The channel can be opened, however, by certain anesthetics, membrane stretching, intracellular acidosis, and heat. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-215195099-A-C is Benign according to our data. Variant chr1-215195099-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 785792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK2	NM_001017425.3	c.963+7A>C		splice_region_variant, intron_variant	Intron 6 of 6	ENST00000444842.7	NP_001017425.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK2	ENST00000444842.7	c.963+7A>C		splice_region_variant, intron_variant	Intron 6 of 6	1	NM_001017425.3	ENSP00000394033.2

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152210 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00129 AC: 305 AN: 235992 AF XY: 0.00146

Gnomad AFR exome AF: 0.000254

Gnomad AMR exome AF: 0.000327

Gnomad ASJ exome AF: 0.000542

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.000885

GnomAD4 exome AF: 0.00192 AC: 2758 AN: 1434630 Hom.: 12 Cov.: 29 AF XY: 0.00188 AC XY: 1340 AN XY: 712912

African (AFR) AF: 0.000338 AC: 11 AN: 32542

American (AMR) AF: 0.000294 AC: 12 AN: 40788

Ashkenazi Jewish (ASJ) AF: 0.000318 AC: 8 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 38982

South Asian (SAS) AF: 0.000483 AC: 39 AN: 80718

European-Finnish (FIN) AF: 0.0000573 AC: 3 AN: 52344

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5666

European-Non Finnish (NFE) AF: 0.00237 AC: 2600 AN: 1099324

Other (OTH) AF: 0.00130 AC: 77 AN: 59084

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.00123 AC XY: 92 AN XY: 74504

African (AFR) AF: 0.000457 AC: 19 AN: 41574

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00216 AC: 147 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00181 Hom.: 0

Bravo AF: 0.00146

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.82
CADD	Benign	2.5
DANN	Benign	0.59
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
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: rs80246222; hg19: chr1-215368442;