Genetic Variant KCNC3:p.Pro732Pro (chr19-50320324-G-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_004977.3(KCNC3):c.2196C>A(p.Pro732Pro) variant causes a synonymous 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P732P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000077 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.692

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

KCNC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 19-50320324-G-T is Benign according to our data. Variant chr19-50320324-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3778081.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.692 with no splicing effect.

BS2

High AC in GnomAdExome4 at 13 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.2196C>A	p.Pro732Pro	synonymous	Exon 4 of 5	NP_004968.2
KCNC3	NM_001372305.1		c.1968C>A	p.Pro656Pro	synonymous	Exon 4 of 5	NP_001359234.1
KCNC3	NR_110912.2		n.260+269C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.2196C>A	p.Pro732Pro	synonymous	Exon 4 of 5	ENSP00000434241.1	Q14003
KCNC3	ENST00000670667.1		c.2170+269C>A		intron	N/A	ENSP00000499301.1	A0A590UJ62
KCNC3	ENST00000376959.6	TSL:5	c.2170+269C>A		intron	N/A	ENSP00000366158.2	E7ETH1

Frequencies

GnomAD3 genomes

AF:

0.00000772

AC:

AN:

129616

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000287

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000428

AC:

AN:

303490

Hom.:

Cov.:

AF XY:

0.0000444

AC XY:

AN XY:

157512

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8840

American (AMR)

AF:

0.00

AC:

AN:

12878

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7832

East Asian (EAS)

AF:

0.00

AC:

AN:

14820

South Asian (SAS)

AF:

0.0000803

AC:

AN:

37340

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1650

European-Non Finnish (NFE)

AF:

0.0000533

AC:

AN:

187662

Other (OTH)

AF:

0.00

AC:

AN:

16010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00000772

AC:

AN:

129616

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

62018

show subpopulations

African (AFR)

AF:

0.0000287

AC:

AN:

34874

American (AMR)

AF:

0.00

AC:

AN:

13152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3172

East Asian (EAS)

AF:

0.00

AC:

AN:

3596

South Asian (SAS)

AF:

0.00

AC:

AN:

3356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

60476

Other (OTH)

AF:

0.00

AC:

AN:

1788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.3

(source)

DANN

Benign

0.75

PhyloP100

0.69

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