rs761806977

chr19-50329060-G-Achr19-50329060-G-Cchr19-50329060-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004977.3(KCNC3):c.23C>T(p.Ser8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,311,576 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S8W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000029 ( 0 hom., cov: 22)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22133043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNC3	NM_004977.3 linkuse as main transcript	c.23C>T	p.Ser8Leu	missense_variant	1/5	ENST00000477616.2
KCNC3	NM_001372305.1 linkuse as main transcript	c.-206C>T		5_prime_UTR_variant	1/5
KCNC3	NR_110912.2 linkuse as main transcript	n.68+4409C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
KCNC3	ENST00000477616.2 linkuse as main transcript	c.23C>T	p.Ser8Leu	missense_variant	1/5	1	NM_004977.3
KCNC3	ENST00000670667.1 linkuse as main transcript	c.23C>T	p.Ser8Leu	missense_variant	1/4			P3
KCNC3	ENST00000376959.6 linkuse as main transcript	c.23C>T	p.Ser8Leu	missense_variant	1/5	5		A2
KCNC3	ENST00000474951.1 linkuse as main transcript	c.-75+4409C>T		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000287

AC:

AN:

139268

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:

0.00

Gnomad FIN

AF:

0.000114

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000472

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000328

AC:

AN:

61032

Hom.:

AF XY:

0.0000279

AC XY:

AN XY:

35816

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 SAS exome

AF:

0.0000700

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000455

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000938

AC:

AN:

1172308

Hom.:

Cov.:

AF XY:

0.0000104

AC XY:

AN XY:

574684

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000394

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000836

Gnomad4 OTH exome

AF:

0.0000212

GnomAD4 genome

AF:

0.0000287

AC:

AN:

139268

Hom.:

Cov.:

AF XY:

0.0000148

AC XY:

AN XY:

67384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000114

Gnomad4 NFE

AF:

0.0000472

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000688

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNC3 protein function. This variant has not been reported in the literature in individuals affected with KCNC3-related conditions. This variant is present in population databases (rs761806977, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 8 of the KCNC3 protein (p.Ser8Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.67

T;T

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.22

T;T

MetaSVM

Uncertain

0.13

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.20

T;T

Sift4G

Uncertain

0.026

D;D

Polyphen

0.94

.;P

Vest4

0.23

MutPred

0.38

Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);

MVP

0.55

ClinPred

0.13

GERP RS

-0.00056

Varity_R

0.057

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over