19-50323193-G-C

Position:

chr19-50323193-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_004977.3(KCNC3):c.1760C>G(p.Pro587Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,523,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.32

Variant links:

Genes affected

KCNC3 (HGNC:6235): (potassium voltage-gated channel subfamily C member 3) The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and is comprised of four subfamilies. Based on sequence similarity, this gene is similar to one of these subfamilies, namely the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes. Alternate splicing results in several transcript variants. [provided by RefSeq, Mar 2014]

KCNC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19623056).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000372 (51/1370898) while in subpopulation MID AF= 0.000744 (3/4034). AF 95% confidence interval is 0.000202. There are 0 homozygotes in gnomad4_exome. There are 34 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC3	NM_004977.3 link	c.1760C>G	p.Pro587Arg	missense_variant	2/5	ENST00000477616.2	NP_004968.2	Q14003
KCNC3	NM_001372305.1 link	c.1532C>G	p.Pro511Arg	missense_variant	2/5		NP_001359234.1
KCNC3	NR_110912.2 link	n.69-2409C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNC3	ENST00000477616.2 link	c.1760C>G	p.Pro587Arg	missense_variant	2/5	1	NM_004977.3	ENSP00000434241.1	Q14003
KCNC3	ENST00000670667.1 link	c.1760C>G	p.Pro587Arg	missense_variant	2/4			ENSP00000499301.1	A0A590UJ62
KCNC3	ENST00000376959.6 link	c.1760C>G	p.Pro587Arg	missense_variant	2/5	5		ENSP00000366158.2	E7ETH1
KCNC3	ENST00000474951.1 link	c.-74-2409C>G		intron_variant		2		ENSP00000432438.1	E9PQY4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000442

AC:

AN:

135648

Hom.:

AF XY:

0.0000672

AC XY:

AN XY:

74350

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000407

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000377

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000372

AC:

AN:

1370898

Hom.:

Cov.:

AF XY:

0.0000502

AC XY:

AN XY:

677006

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000279

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000175

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000427

Hom.:

ExAC

AF:

0.0000312

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNC3 protein function. This variant has not been reported in the literature in individuals affected with KCNC3-related conditions. This variant is present in population databases (rs554197864, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 587 of the KCNC3 protein (p.Pro587Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.75

T;T

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.20

T;T

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

1.5

.;L

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.12

T;T

Polyphen

0.0040

B;B

Vest4

0.093

MutPred

0.20

Loss of glycosylation at P587 (P = 0.0339);Loss of glycosylation at P587 (P = 0.0339);

MVP

0.42

ClinPred

0.12

GERP RS

2.3

Varity_R

0.11

gMVP

0.66

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