chr19-50328956-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004977.3(KCNC3):c.127C>T(p.Pro43Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 877,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0480

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031967282).

BP6

Variant 19-50328956-G-A is Benign according to our data. Variant chr19-50328956-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000985 (144/146212) while in subpopulation AFR AF = 0.00333 (136/40790). AF 95% confidence interval is 0.00288. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAd4 at 144 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3 link	c.127C>T	p.Pro43Ser	missense_variant	Exon 1 of 5	ENST00000477616.2	NP_004968.2	Q14003
KCNC3	NM_001372305.1 link	c.-102C>T		5_prime_UTR_variant	Exon 1 of 5		NP_001359234.1
KCNC3	NR_110912.2 link	n.68+4513C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNC3	ENST00000477616.2 link	c.127C>T	p.Pro43Ser	missense_variant	Exon 1 of 5	1	NM_004977.3	ENSP00000434241.1	Q14003
KCNC3	ENST00000670667.1 link	c.127C>T	p.Pro43Ser	missense_variant	Exon 1 of 4			ENSP00000499301.1	A0A590UJ62
KCNC3	ENST00000376959.6 link	c.127C>T	p.Pro43Ser	missense_variant	Exon 1 of 5	5		ENSP00000366158.2	E7ETH1
KCNC3	ENST00000474951.1 link	c.-75+4513C>T		intron_variant	Intron 1 of 3	2		ENSP00000432438.1	E9PQY4

Frequencies

GnomAD3 genomes

AF:

0.000958

AC:

140

AN:

146122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000339

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:

0.00

Gnomad OTH

AF:

0.00150

GnomAD4 exome

AF:

0.0000971

AC:

AN:

731360

Hom.:

Cov.:

AF XY:

0.0000992

AC XY:

AN XY:

352716

show subpopulations

African (AFR)

AF:

0.00385

AC:

AN:

14022

American (AMR)

AF:

0.00

AC:

AN:

2802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6406

East Asian (EAS)

AF:

0.00

AC:

AN:

9760

South Asian (SAS)

AF:

0.00

AC:

AN:

17610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8672

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1710

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

643938

Other (OTH)

AF:

0.000378

AC:

AN:

26440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

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:

0.000985

AC:

144

AN:

146212

Hom.:

Cov.:

AF XY:

0.000928

AC XY:

AN XY:

71140

show subpopulations

African (AFR)

AF:

0.00333

AC:

136

AN:

40790

American (AMR)

AF:

0.000339

AC:

AN:

14758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3398

East Asian (EAS)

AF:

0.00

AC:

AN:

5032

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65720

Other (OTH)

AF:

0.00149

AC:

AN:

2020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.00135

Hom.:

Bravo

AF:

0.00122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 13, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 25, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.42

T;T

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.032

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.0

.;N

PhyloP100

0.048

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.73

N;N

REVEL

Benign

0.27

Sift

Benign

0.039

D;D

Sift4G

Benign

0.60

T;T

Polyphen

0.0

.;B

Vest4

0.14

MutPred

0.21

Gain of phosphorylation at P43 (P = 0.011);Gain of phosphorylation at P43 (P = 0.011);

MVP

0.57

ClinPred

0.077

GERP RS

-1.1

PromoterAI

-0.070

Neutral

(source)

Varity_R

0.047

gMVP

0.14

Mutation Taster

=84/16

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over