Genetic Variant KCNC3:p.Gln41His (chr19-50328960-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004977.3(KCNC3):c.123G>C(p.Gln41His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 800,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000012 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.85

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19324744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNC3	NM_004977.3 link	c.123G>C	p.Gln41His	missense_variant	Exon 1 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1 link	c.-106G>C		5_prime_UTR_variant	Exon 1 of 5		NP_001359234.1
KCNC3	NR_110912.2 link	n.68+4509G>C		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KCNC3	ENST00000477616.2 link	c.123G>C	p.Gln41His	missense_variant	Exon 1 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1 link	c.123G>C	p.Gln41His	missense_variant	Exon 1 of 4			ENSP00000499301.1
KCNC3	ENST00000376959.6 link	c.123G>C	p.Gln41His	missense_variant	Exon 1 of 5	5		ENSP00000366158.2
KCNC3	ENST00000474951.1 link	c.-75+4509G>C		intron_variant	Intron 1 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000125

AC:

AN:

800792

Hom.:

Cov.:

AF XY:

0.00000258

AC XY:

AN XY:

387464

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

15256

American (AMR)

AF:

0.00

AC:

AN:

3508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7622

East Asian (EAS)

AF:

0.00

AC:

AN:

12426

South Asian (SAS)

AF:

0.00

AC:

AN:

20988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1910

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

697976

Other (OTH)

AF:

0.0000338

AC:

AN:

29556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.46

T;T

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.19

T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

0.0

.;N

PhyloP100

1.8

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.67

N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.043

D;D

Polyphen

0.0020

.;B

Vest4

0.26

MutPred

0.22

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.61

ClinPred

0.15

GERP RS

1.1

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.13

gMVP

0.14

Mutation Taster

=97/3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over