chr19-50320305-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.2215G>A(p.Gly739Ser) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G739G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000042 ( 0 hom., cov: 16)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.924

Publications

1 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, ClinGen, Orphanet

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=0.14472213).

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000886 (7/789718) while in subpopulation AMR AF = 0.000189 (3/15844). AF 95% confidence interval is 0.000051. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 11. 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 5 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.2215G>A	p.Gly739Ser	missense	Exon 4 of 5	NP_004968.2
KCNC3	NM_001372305.1		c.1987G>A	p.Gly663Ser	missense	Exon 4 of 5	NP_001359234.1
KCNC3	NR_110912.2		n.260+288G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.2215G>A	p.Gly739Ser	missense	Exon 4 of 5	ENSP00000434241.1	Q14003
KCNC3	ENST00000670667.1		c.2170+288G>A		intron	N/A	ENSP00000499301.1	A0A590UJ62
KCNC3	ENST00000376959.6	TSL:5	c.2170+288G>A		intron	N/A	ENSP00000366158.2	E7ETH1

Frequencies

GnomAD3 genomes

AF:

0.0000417

AC:

AN:

119910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000211

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:

0.0000495

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000405

AC:

AN:

49352

AF XY:

0.0000394

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000886

AC:

AN:

789718

Hom.:

Cov.:

AF XY:

0.0000103

AC XY:

AN XY:

387758

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19452

American (AMR)

AF:

0.000189

AC:

AN:

15844

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14670

East Asian (EAS)

AF:

0.00

AC:

AN:

29626

South Asian (SAS)

AF:

0.00

AC:

AN:

39074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29722

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2708

European-Non Finnish (NFE)

AF:

0.00000664

AC:

AN:

602816

Other (OTH)

AF:

0.00

AC:

AN:

35806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

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:

0.0000417

AC:

AN:

119922

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

55794

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30376

American (AMR)

AF:

0.000210

AC:

AN:

9508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3204

East Asian (EAS)

AF:

0.00

AC:

AN:

4034

South Asian (SAS)

AF:

0.00

AC:

AN:

3606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6022

Middle Eastern (MID)

AF:

0.00

AC:

AN:

196

European-Non Finnish (NFE)

AF:

0.0000495

AC:

AN:

60552

Other (OTH)

AF:

0.00

AC:

AN:

1600

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000843

Hom.:

ExAC

AF:

0.0000138

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.080

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.14

MetaSVM

Uncertain

-0.021

MutationAssessor

Benign

0.0

PhyloP100

0.92

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.36

REVEL

Uncertain

0.44

Sift

Benign

0.088

Sift4G

Benign

0.33

Polyphen

0.17

Vest4

0.26

MutPred

0.063

Gain of phosphorylation at G739 (P = 0.0162)

MVP

0.82

ClinPred

0.066

GERP RS

1.3

Varity_R

0.072

gMVP

0.20

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over