Genetic Variant KCNC3:p.Ser8Trp (chr19-50329060-G-C) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_004977.3(KCNC3):c.23C>G(p.Ser8Trp) variant causes a missense 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S8L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 1 hom., cov: 22)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

KCNC3
NM_004977.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.40

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 13
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

KCNC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 447623.

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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 30 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004977.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNC3	NM_004977.3	MANE Select	c.23C>G	p.Ser8Trp	missense	Exon 1 of 5	NP_004968.2
KCNC3	NM_001372305.1		c.-206C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001359234.1
KCNC3	NM_001372305.1		c.-206C>G		5_prime_UTR	Exon 1 of 5	NP_001359234.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.23C>G	p.Ser8Trp	missense	Exon 1 of 5	ENSP00000434241.1
KCNC3	ENST00000670667.1		c.23C>G	p.Ser8Trp	missense	Exon 1 of 4	ENSP00000499301.1
KCNC3	ENST00000376959.6	TSL:5	c.23C>G	p.Ser8Trp	missense	Exon 1 of 5	ENSP00000366158.2

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

GnomAD2 exomes

AF:

0.0000983

AC:

AN:

61032

AF XY:

0.0000838

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 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

African (AFR)

AF:

0.00

AC:

AN:

24396

American (AMR)

AF:

0.0000503

AC:

AN:

19900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19522

East Asian (EAS)

AF:

0.00199

AC:

AN:

25076

South Asian (SAS)

AF:

0.00

AC:

AN:

50806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3242

European-Non Finnish (NFE)

AF:

0.00000627

AC:

AN:

956984

Other (OTH)

AF:

0.00180

AC:

AN:

47276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000215

AC:

AN:

139386

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

67494

show subpopulations

African (AFR)

AF:

0.0000258

AC:

AN:

38768

American (AMR)

AF:

0.000500

AC:

AN:

14010

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3272

East Asian (EAS)

AF:

0.00416

AC:

AN:

4082

South Asian (SAS)

AF:

0.000261

AC:

AN:

3834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63606

Other (OTH)

AF:

0.00209

AC:

AN:

1914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

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

Jan 26, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNC3: PP2, PP3, BS1

Inborn genetic diseases

Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 14, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNC3-related disorder

Benign:1

Mar 23, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.13

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.070

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

0.0

PhyloP100

1.4

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.31

Sift

Benign

0.28

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.29

MutPred

0.38

Loss of phosphorylation at S8 (P = 0.0187)

MVP

0.84

ClinPred

0.087

GERP RS

-0.00056

PromoterAI

-0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.067

gMVP

0.24

Mutation Taster

=91/9

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over