Variant 16-84222498-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_172347.3(KCNG4):c.1279C>T(p.Arg427Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R427H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

KCNG4
NM_172347.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.160

Variant links:

Genes affected

KCNG4 (HGNC:19697): (potassium voltage-gated channel modifier subfamily G member 4) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily G. This member functions as a modulatory subunit. The gene has strong expression in brain. Multiple alternatively spliced variants have been found in normal and cancerous tissues. [provided by RefSeq, Jul 2008]

KCNG4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30266353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNG4	NM_172347.3 linkuse as main transcript	c.1279C>T	p.Arg427Cys	missense_variant	3/3	ENST00000308251.6	NP_758857.1	Q8TDN1-1Q547S7Q32MC1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNG4	ENST00000308251.6 linkuse as main transcript	c.1279C>T	p.Arg427Cys	missense_variant	3/3	1	NM_172347.3	ENSP00000312129.4		Q8TDN1-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000879

AC:

AN:

250182

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

135386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461208

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

726876

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000869

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Jul 12, 2022

The c.1279C>T (p.R427C) alteration is located in exon 3 (coding exon 2) of the KCNG4 gene. This alteration results from a C to T substitution at nucleotide position 1279, causing the arginine (R) at amino acid position 427 to be replaced by a cysteine (C). 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

Benign

0.14

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.021

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.59

MutationAssessor

Pathogenic

3.4

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.8

REVEL

Benign

0.18

Sift

Uncertain

0.0020

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.18

MutPred

0.41

Gain of catalytic residue at P426 (P = 0.0086);

MVP

0.48

MPC

0.061

ClinPred

0.71

GERP RS

2.4

Varity_R

0.59

gMVP

0.87

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