NM_004977.3:c.2206C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_004977.3(KCNC3):c.2206C>T(p.Arg736Cys) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R736H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000024 ( 0 hom., cov: 16)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.70

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: 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30502015).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3 link	c.2206C>T	p.Arg736Cys	missense_variant	Exon 4 of 5	ENST00000477616.2	NP_004968.2	Q14003
KCNC3	NM_001372305.1 link	c.1978C>T	p.Arg660Cys	missense_variant	Exon 4 of 5		NP_001359234.1
KCNC3	NR_110912.2 link	n.260+279C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNC3	ENST00000477616.2 link	c.2206C>T	p.Arg736Cys	missense_variant	Exon 4 of 5	1	NM_004977.3	ENSP00000434241.1	Q14003
KCNC3	ENST00000670667.1 link	c.2170+279C>T		intron_variant	Intron 3 of 3			ENSP00000499301.1	A0A590UJ62
KCNC3	ENST00000376959.6 link	c.2170+279C>T		intron_variant	Intron 3 of 4	5		ENSP00000366158.2	E7ETH1
KCNC3	ENST00000474951.1 link	c.118+279C>T		intron_variant	Intron 2 of 3	2		ENSP00000432438.1	E9PQY4

Frequencies

GnomAD3 genomes

AF:

0.0000237

AC:

AN:

126460

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:

0.000320

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000334

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000190

AC:

AN:

52688

AF XY:

0.0000372

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:

0.0000500

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

427814

Hom.:

Cov.:

AF XY:

0.0000327

AC XY:

AN XY:

214378

show subpopulations

African (AFR)

AF:

0.000174

AC:

AN:

11504

American (AMR)

AF:

0.00

AC:

AN:

12056

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8080

East Asian (EAS)

AF:

0.00

AC:

AN:

14044

South Asian (SAS)

AF:

0.000107

AC:

AN:

37282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1602

European-Non Finnish (NFE)

AF:

0.0000194

AC:

AN:

308638

Other (OTH)

AF:

0.00

AC:

AN:

19500

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:

0.0000237

AC:

AN:

126460

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

60340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

34020

American (AMR)

AF:

0.00

AC:

AN:

12550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3150

East Asian (EAS)

AF:

0.00

AC:

AN:

3356

South Asian (SAS)

AF:

0.000320

AC:

AN:

3124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000334

AC:

AN:

59864

Other (OTH)

AF:

0.00

AC:

AN:

1766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2206C>T (p.R736C) alteration is located in exon 4 (coding exon 4) of the KCNC3 gene. This alteration results from a C to T substitution at nucleotide position 2206, causing the arginine (R) at amino acid position 736 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.097

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.31

MetaSVM

Uncertain

0.068

MutationAssessor

Benign

0.0

PhyloP100

1.7

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.21

REVEL

Uncertain

0.35

Sift

Benign

0.12

Sift4G

Uncertain

0.056

Polyphen

0.94

Vest4

0.16

MutPred

0.22

Loss of solvent accessibility (P = 0.0352);

MVP

0.75

ClinPred

0.25

GERP RS

2.3

Varity_R

0.11

gMVP

0.13

Mutation Taster

=88/12

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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NM_004977.3:c.2206C>T

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