Genetic Variant NM_004977.3:c.23C>A (chr19-50329060-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_004977.3(KCNC3):c.23C>A(p.Ser8*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000256 in 1,172,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S8S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000026 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.40

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_pathogenic. The variant received 6 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

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.23C>A	p.Ser8*	stop_gained	Exon 1 of 5	NP_004968.2
KCNC3	NM_001372305.1		c.-206C>A		5_prime_UTR	Exon 1 of 5	NP_001359234.1
KCNC3	NR_110912.2		n.68+4409C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.23C>A	p.Ser8*	stop_gained	Exon 1 of 5	ENSP00000434241.1
KCNC3	ENST00000670667.1		c.23C>A	p.Ser8*	stop_gained	Exon 1 of 4	ENSP00000499301.1
KCNC3	ENST00000376959.6	TSL:5	c.23C>A	p.Ser8*	stop_gained	Exon 1 of 5	ENSP00000366158.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000256

AC:

AN:

1172304

Hom.:

Cov.:

AF XY:

0.00000348

AC XY:

AN XY:

574680

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24398

American (AMR)

AF:

0.00

AC:

AN:

19900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19522

East Asian (EAS)

AF:

0.00

AC:

AN:

25078

South Asian (SAS)

AF:

0.00

AC:

AN:

50804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3242

European-Non Finnish (NFE)

AF:

0.00000313

AC:

AN:

956982

Other (OTH)

AF:

0.00

AC:

AN:

47278

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

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.24

Eigen_PC

Benign

-0.025

FATHMM_MKL

Benign

0.45

PhyloP100

1.4

Vest4

0.42

GERP RS

-0.00056

PromoterAI

0.0038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=30/170

disease causing (fs/PTC)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over