Genetic Variant NM_004977.3:c.1954G>C (chr19-50322999-C-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

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

The NM_004977.3(KCNC3):c.1954G>C(p.Glu652Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000429 in 1,397,994 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. E652K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.32

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:

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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=0.31711453).

BS2

High AC in GnomAdExome4 at 6 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.1954G>C	p.Glu652Gln	missense	Exon 2 of 5	NP_004968.2
KCNC3	NM_001372305.1		c.1726G>C	p.Glu576Gln	missense	Exon 2 of 5	NP_001359234.1
KCNC3	NR_110912.2		n.69-2215G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.1954G>C	p.Glu652Gln	missense	Exon 2 of 5	ENSP00000434241.1
KCNC3	ENST00000670667.1		c.1954G>C	p.Glu652Gln	missense	Exon 2 of 4	ENSP00000499301.1
KCNC3	ENST00000376959.6	TSL:5	c.1954G>C	p.Glu652Gln	missense	Exon 2 of 5	ENSP00000366158.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000429

AC:

AN:

1397994

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689622

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31624

American (AMR)

AF:

0.00

AC:

AN:

35876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25158

East Asian (EAS)

AF:

0.00

AC:

AN:

35818

South Asian (SAS)

AF:

0.00

AC:

AN:

79208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4966

European-Non Finnish (NFE)

AF:

0.00000556

AC:

AN:

1079308

Other (OTH)

AF:

0.00

AC:

AN:

57912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.32

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

1.6

PhyloP100

4.3

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.44

Sift

Uncertain

0.0020

Sift4G

Benign

0.14

Polyphen

0.98

Vest4

0.23

MutPred

0.13

Loss of helix (P = 0.079)

MVP

0.81

ClinPred

0.78

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.23

gMVP

0.50

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over