chr12-21765733-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_004982.4(KCNJ8):ā€‹c.1265C>Gā€‹(p.Ser422Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S422L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

KCNJ8
NM_004982.4 missense

Scores

3
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.48
Variant links:
Genes affected
KCNJ8 (HGNC:6269): (potassium inwardly rectifying channel subfamily J member 8) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins. Defects in this gene may be a cause of J-wave syndromes and sudden infant death syndrome (SIDS). [provided by RefSeq, May 2012]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-21765733-G-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.24593931).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNJ8NM_004982.4 linkc.1265C>G p.Ser422Trp missense_variant Exon 3 of 3 ENST00000240662.3 NP_004973.1 Q15842A0A024RAV6
LOC105369689XR_007063241.1 linkn.631+5648G>C intron_variant Intron 2 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNJ8ENST00000240662.3 linkc.1265C>G p.Ser422Trp missense_variant Exon 3 of 3 1 NM_004982.4 ENSP00000240662.2 Q15842

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251364
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135850
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461564
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727106
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.016
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
18
DANN
Uncertain
0.97
DEOGEN2
Benign
0.36
T
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.23
FATHMM_MKL
Benign
0.47
N
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.040
D
MetaRNN
Benign
0.25
T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
0.34
N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.4
N
REVEL
Benign
0.26
Sift
Uncertain
0.0060
D
Sift4G
Uncertain
0.037
D
Polyphen
0.87
P
Vest4
0.42
MutPred
0.34
Loss of relative solvent accessibility (P = 0.0186);
MVP
0.63
MPC
1.5
ClinPred
0.37
T
GERP RS
4.5
Varity_R
0.084
gMVP
0.70

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.

Other links and lift over

dbSNP: rs72554071; hg19: chr12-21918667; API