19-50320275-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_004977.3(KCNC3):c.2245G>A(p.Ala749Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 16)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.92

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25157288).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000556 (51/916716) while in subpopulation NFE AF = 0.0000662 (48/724782). AF 95% confidence interval is 0.0000513. There are 0 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 13. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3 link	c.2245G>A	p.Ala749Thr	missense_variant	Exon 4 of 5	ENST00000477616.2	NP_004968.2	Q14003
KCNC3	NM_001372305.1 link	c.2017G>A	p.Ala673Thr	missense_variant	Exon 4 of 5		NP_001359234.1
KCNC3	NR_110912.2 link	n.260+318G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNC3	ENST00000477616.2 link	c.2245G>A	p.Ala749Thr	missense_variant	Exon 4 of 5	1	NM_004977.3	ENSP00000434241.1	Q14003
KCNC3	ENST00000670667.1 link	c.2170+318G>A		intron_variant	Intron 3 of 3			ENSP00000499301.1	A0A590UJ62
KCNC3	ENST00000376959.6 link	c.2170+318G>A		intron_variant	Intron 3 of 4	5		ENSP00000366158.2	E7ETH1
KCNC3	ENST00000474951.1 link	c.118+318G>A		intron_variant	Intron 2 of 3	2		ENSP00000432438.1	E9PQY4

Frequencies

GnomAD3 genomes

AF:

0.0000467

AC:

AN:

128458

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000872

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000802

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000528

AC:

AN:

56842

AF XY:

0.00

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:

0.0000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000556

AC:

AN:

916716

Hom.:

Cov.:

AF XY:

0.0000562

AC XY:

AN XY:

444648

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21636

American (AMR)

AF:

0.00

AC:

AN:

15058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14720

East Asian (EAS)

AF:

0.00

AC:

AN:

28858

South Asian (SAS)

AF:

0.0000268

AC:

AN:

37340

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3094

European-Non Finnish (NFE)

AF:

0.0000662

AC:

AN:

724782

Other (OTH)

AF:

0.0000510

AC:

AN:

39240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000467

AC:

AN:

128458

Hom.:

Cov.:

AF XY:

0.0000328

AC XY:

AN XY:

60942

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.0000872

AC:

AN:

11462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3280

East Asian (EAS)

AF:

0.00

AC:

AN:

4102

South Asian (SAS)

AF:

0.00

AC:

AN:

3696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.0000802

AC:

AN:

62336

Other (OTH)

AF:

0.00

AC:

AN:

1776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spinocerebellar ataxia type 13

Uncertain:1

Nov 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

Eigen

Benign

0.014

Eigen_PC

Benign

0.0061

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.48

M_CAP

Pathogenic

0.71

MetaRNN

Benign

0.25

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

0.0

PhyloP100

2.9

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.34

REVEL

Uncertain

0.36

Sift

Benign

0.10

Sift4G

Benign

0.25

Polyphen

0.96

Vest4

0.30

MutPred

0.10

Loss of helix (P = 0.0376);

MVP

0.84

ClinPred

0.14

GERP RS

2.3

Varity_R

0.075

gMVP

0.22

Mutation Taster

=96/4

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.

19-50320275-C-T

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