21-37625289-A-G

Position:

chr21-37625289-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2

The NM_002240.5(KCNJ6):c.1142T>C(p.Leu381Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

KCNJ6
NM_002240.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.95

Variant links:

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 links:

ENSG00000286717 (HGNC:):

ENSG00000286717 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNJ6. . Gene score misZ 3.7134 (greater than the threshold 3.09). Trascript score misZ 4.9887 (greater than threshold 3.09). GenCC has associacion of gene with Keppen-Lubinsky syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ6	NM_002240.5 linkuse as main transcript	c.1142T>C	p.Leu381Pro	missense_variant	4/4	ENST00000609713.2	NP_002231.1	P48051
KCNJ6-AS1	NR_183540.1 linkuse as main transcript	n.408-73266A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNJ6	ENST00000609713.2 linkuse as main transcript	c.1142T>C	p.Leu381Pro	missense_variant	4/4	1	NM_002240.5	ENSP00000477437.1	P48051
KCNJ6	ENST00000645093.1 linkuse as main transcript	c.1142T>C	p.Leu381Pro	missense_variant	5/5			ENSP00000493772.1	P48051
ENSG00000286717	ENST00000667151.1 linkuse as main transcript	n.161-21258A>G		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000137

AC:

AN:

248948

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000204

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000127

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000880

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 19, 2024

Variant summary: KCNJ6 c.1142T>C (p.Leu381Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 248948 control chromosomes. To our knowledge, no occurrence of c.1142T>C in individuals affected with Keppen-Lubinsky Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1512840). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 30, 2022

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 381 of the KCNJ6 protein (p.Leu381Pro). ClinVar contains an entry for this variant (Variation ID: 1512840). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with KCNJ6-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.81

.;T

M_CAP

Benign

0.041

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.77

Sift4G

Benign

0.28

T;.

Polyphen

0.99

D;D

Vest4

0.56

MVP

0.71

MPC

2.7

ClinPred

0.43

GERP RS

6.0

Varity_R

0.46

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over