rs2836016

Variant names:

• chr21-37840718-G-A
• rs2836016
• NM_002240.5:c.-27-9C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-37840718-G-A
• chr21-37840718-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002240.5(KCNJ6):​c.-27-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 1,507,856 control chromosomes in the GnomAD database, including 247,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.59 (26473 hom., cov: 33)
  • Exomes 𝑓: 0.57 (221026 hom.)
• Consequence: KCNJ6 NM_002240.5 intron
• Scores: Splicing: ADA: 0.0002224
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.906
• Publications: 18 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)

ENSG00000292435 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 21-37840718-G-A is Benign according to our data. Variant chr21-37840718-G-A is described in ClinVar as Benign. ClinVar VariationId is 1226048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ6	NM_002240.5	c.-27-9C>T		intron_variant	Intron 1 of 3	ENST00000609713.2	NP_002231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ6	ENST00000609713.2	c.-27-9C>T		intron_variant	Intron 1 of 3	1	NM_002240.5	ENSP00000477437.1

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89359 AN: 151958 Hom.: 26464 Cov.: 33

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.608

GnomAD2 exomes AF: 0.591 AC: 142673 AN: 241300 AF XY: 0.590

Gnomad AFR exome AF: 0.615

Gnomad AMR exome AF: 0.594

Gnomad ASJ exome AF: 0.671

Gnomad EAS exome AF: 0.786

Gnomad FIN exome AF: 0.524

Gnomad NFE exome AF: 0.559

Gnomad OTH exome AF: 0.592

GnomAD4 exome AF: 0.567 AC: 769313 AN: 1355780 Hom.: 221026 Cov.: 20 AF XY: 0.569 AC XY: 386834 AN XY: 680092

African (AFR) AF: 0.607 AC: 18834 AN: 31030

American (AMR) AF: 0.591 AC: 25237 AN: 42704

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 16763 AN: 25146

East Asian (EAS) AF: 0.795 AC: 30757 AN: 38676

South Asian (SAS) AF: 0.607 AC: 49619 AN: 81790

European-Finnish (FIN) AF: 0.526 AC: 27795 AN: 52840

Middle Eastern (MID) AF: 0.632 AC: 3479 AN: 5508

European-Non Finnish (NFE) AF: 0.551 AC: 563154 AN: 1021572

Other (OTH) AF: 0.596 AC: 33675 AN: 56514

GnomAD4 genome AF: 0.588 AC: 89411 AN: 152076 Hom.: 26473 Cov.: 33 AF XY: 0.588 AC XY: 43697 AN XY: 74328

African (AFR) AF: 0.610 AC: 25300 AN: 41474

American (AMR) AF: 0.610 AC: 9318 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2366 AN: 3472

East Asian (EAS) AF: 0.780 AC: 4040 AN: 5180

South Asian (SAS) AF: 0.624 AC: 3008 AN: 4820

European-Finnish (FIN) AF: 0.528 AC: 5561 AN: 10542

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37714 AN: 67984

Other (OTH) AF: 0.608 AC: 1286 AN: 2114

Alfa AF: 0.570 Hom.: 8376

Bravo AF: 0.597

Asia WGS AF: 0.674 AC: 2345 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

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	-0.41
CADD	Benign	17
DANN	Benign	0.60
PhyloP100		0.91
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.0040
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: rs2836016; hg19: chr21-39213020; COSMIC: COSV55709759;