rs761806977

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004977.3(KCNC3):c.23C>T(p.Ser8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,311,576 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. S8W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000029 ( 0 hom., cov: 22)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22133043).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3 link	c.23C>T	p.Ser8Leu	missense_variant	Exon 1 of 5	ENST00000477616.2	NP_004968.2	Q14003
KCNC3	NM_001372305.1 link	c.-206C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5		NP_001359234.1
KCNC3	NM_001372305.1 link	c.-206C>T		5_prime_UTR_variant	Exon 1 of 5		NP_001359234.1
KCNC3	NR_110912.2 link	n.68+4409C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNC3	ENST00000477616.2 link	c.23C>T	p.Ser8Leu	missense_variant	Exon 1 of 5	1	NM_004977.3	ENSP00000434241.1	Q14003
KCNC3	ENST00000670667.1 link	c.23C>T	p.Ser8Leu	missense_variant	Exon 1 of 4			ENSP00000499301.1	A0A590UJ62
KCNC3	ENST00000376959.6 link	c.23C>T	p.Ser8Leu	missense_variant	Exon 1 of 5	5		ENSP00000366158.2	E7ETH1
KCNC3	ENST00000474951.1 link	c.-75+4409C>T		intron_variant	Intron 1 of 3	2		ENSP00000432438.1	E9PQY4

Frequencies

GnomAD3 genomes

AF:

0.0000287

AC:

AN:

139268

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:

0.00

Gnomad FIN

AF:

0.000114

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000472

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000328

AC:

AN:

61032

AF XY:

0.0000279

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000455

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000938

AC:

AN:

1172308

Hom.:

Cov.:

AF XY:

0.0000104

AC XY:

AN XY:

574684

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24398

American (AMR)

AF:

0.00

AC:

AN:

19900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19522

East Asian (EAS)

AF:

0.00

AC:

AN:

25078

South Asian (SAS)

AF:

0.0000394

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:

0.00000836

AC:

AN:

956984

Other (OTH)

AF:

0.0000212

AC:

AN:

47278

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

Exome 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

GnomAD4 genome

AF:

0.0000287

AC:

AN:

139268

Hom.:

Cov.:

AF XY:

0.0000148

AC XY:

AN XY:

67384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38678

American (AMR)

AF:

0.00

AC:

AN:

13982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3272

East Asian (EAS)

AF:

0.00

AC:

AN:

4090

South Asian (SAS)

AF:

0.00

AC:

AN:

3824

European-Finnish (FIN)

AF:

0.000114

AC:

AN:

8766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000472

AC:

AN:

63606

Other (OTH)

AF:

0.00

AC:

AN:

1894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000688

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.23C>T (p.S8L) alteration is located in exon 1 (coding exon 1) of the KCNC3 gene. This alteration results from a C to T substitution at nucleotide position 23, causing the serine (S) at amino acid position 8 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Dec 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 (rs761806977, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 8 of the KCNC3 protein (p.Ser8Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.67

T;T

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.22

T;T

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

0.0

.;N

PhyloP100

1.4

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.20

T;T

Sift4G

Uncertain

0.026

D;D

Polyphen

0.94

.;P

Vest4

0.23

MutPred

0.38

Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);

MVP

0.55

ClinPred

0.13

GERP RS

-0.00056

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.057

gMVP

0.18

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over