Variant 17-21415435-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_021012.5(KCNJ12):c.93C>A(p.Phe31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 69)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNJ12
NM_021012.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.08

Variant links:

Genes affected

KCNJ12 (HGNC:6258): (potassium inwardly rectifying channel subfamily J member 12) This gene encodes an inwardly rectifying K+ channel which may be blocked by divalent cations. This protein is thought to be one of multiple inwardly rectifying channels which contribute to the cardiac inward rectifier current (IK1). The gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

KCNJ12 links:

Genome browser will be placed here

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;

PP2

Missense variant where missense usually causes diseases, KCNJ12

BP4

Computational evidence support a benign effect (MetaRNN=0.34598577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNJ12	NM_021012.5 linkuse as main transcript	c.93C>A	p.Phe31Leu	missense_variant	3/3	ENST00000583088.6
KCNJ12	XM_005256625.6 linkuse as main transcript	c.93C>A	p.Phe31Leu	missense_variant	3/3
KCNJ12	XM_011523831.3 linkuse as main transcript	c.93C>A	p.Phe31Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ12	ENST00000583088.6 linkuse as main transcript	c.93C>A	p.Phe31Leu	missense_variant	3/3	1	NM_021012.5	P1
KCNJ12	ENST00000331718.5 linkuse as main transcript	c.93C>A	p.Phe31Leu	missense_variant	3/3	1		P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461498

Hom.:

Cov.:

201

AF XY:

0.00

AC XY:

AN XY:

727084

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.93C>A (p.F31L) alteration is located in exon 3 (coding exon 1) of the KCNJ12 gene. This alteration results from a C to A substitution at nucleotide position 93, causing the phenylalanine (F) at amino acid position 31 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

1.9

DANN

Uncertain

0.98

DEOGEN2

Benign

0.024

T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.18

M_CAP

Benign

0.021

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

0.98

D;D

PrimateAI

Uncertain

0.76

Sift4G

Benign

0.51

T;T

Polyphen

0.59

P;P

Vest4

0.53

MutPred

0.67

Loss of methylation at K35 (P = 0.1101);Loss of methylation at K35 (P = 0.1101);

MVP

0.17

MPC

0.11

ClinPred

0.55

GERP RS

-7.0

Varity_R

0.41

gMVP

0.79

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over