19-50329060-G-C

Position:

chr19-50329060-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001372305.1(KCNC3):c.-206C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,311,688 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 1 hom., cov: 22)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

KCNC3
NM_001372305.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 1.40

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:

KCNC3 (HGNC:):

KCNC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.069700986).

BP6

Variant 19-50329060-G-C is Benign according to our data. Variant chr19-50329060-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447623.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=2}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000215 (30/139386) while in subpopulation EAS AF= 0.00416 (17/4082). AF 95% confidence interval is 0.00265. There are 1 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC3	NM_004977.3 linkuse as main transcript	c.23C>G	p.Ser8Trp	missense_variant	1/5	ENST00000477616.2	NP_004968.2	Q14003
KCNC3	NM_001372305.1 linkuse as main transcript	c.-206C>G		5_prime_UTR_premature_start_codon_gain_variant	1/5		NP_001359234.1
KCNC3	NM_001372305.1 linkuse as main transcript	c.-206C>G		5_prime_UTR_variant	1/5		NP_001359234.1
KCNC3	NR_110912.2 linkuse as main transcript	n.68+4409C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNC3	ENST00000477616.2 linkuse as main transcript	c.23C>G	p.Ser8Trp	missense_variant	1/5	1	NM_004977.3	ENSP00000434241.1	Q14003
KCNC3	ENST00000670667.1 linkuse as main transcript	c.23C>G	p.Ser8Trp	missense_variant	1/4			ENSP00000499301.1	A0A590UJ62
KCNC3	ENST00000376959.6 linkuse as main transcript	c.23C>G	p.Ser8Trp	missense_variant	1/5	5		ENSP00000366158.2	E7ETH1
KCNC3	ENST00000474951.1 linkuse as main transcript	c.-75+4409C>G		intron_variant		2		ENSP00000432438.1	E9PQY4

Frequencies

GnomAD3 genomes

AF:

0.000215

AC:

AN:

139268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000259

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000501

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00416

Gnomad SAS

AF:

0.000262

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00211

GnomAD3 exomes

AF:

0.0000983

AC:

AN:

61032

Hom.:

AF XY:

0.0000838

AC XY:

AN XY:

35816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000185

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00244

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000121

AC:

142

AN:

1172302

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

574682

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000503

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00199

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000627

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.000215

AC:

AN:

139386

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

67494

show subpopulations

Gnomad4 AFR

AF:

0.0000258

Gnomad4 AMR

AF:

0.000500

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00416

Gnomad4 SAS

AF:

0.000261

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00209

Bravo

AF:

0.000196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	KCNC3: PP2, PP3, BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2024

The c.23C>G (p.S8W) alteration is located in exon 1 (coding exon 1) of the KCNC3 gene. This alteration results from a C to G substitution at nucleotide position 23, causing the serine (S) at amino acid position 8 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 14, 2017

- -

KCNC3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.62

T;T

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.070

T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

0.0

.;N

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.31

Sift

Benign

0.28

T;T

Sift4G

Benign

0.11

T;T

Polyphen

1.0

.;D

Vest4

0.29

MutPred

0.38

Loss of phosphorylation at S8 (P = 0.0187);Loss of phosphorylation at S8 (P = 0.0187);

MVP

0.84

ClinPred

0.087

GERP RS

-0.00056

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.067

gMVP

0.24

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