Genetic Variant KCNC3:p.Asp746Asn (chr19-50320284-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_004977.3(KCNC3):c.2236G>A(p.Asp746Asn) 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 Lovd as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 16)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

KCNC3
NM_004977.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.41

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23249534).

BP6

Variant 19-50320284-C-T is Benign according to our data. Variant chr19-50320284-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000079 (10/126564) while in subpopulation NFE AF= 0.000129 (8/62188). AF 95% confidence interval is 0.0000631. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 16. This position pass quality control queck.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3 link	c.2236G>A	p.Asp746Asn	missense_variant	Exon 4 of 5	ENST00000477616.2	NP_004968.2	Q14003
KCNC3	NM_001372305.1 link	c.2008G>A	p.Asp670Asn	missense_variant	Exon 4 of 5		NP_001359234.1
KCNC3	NR_110912.2 link	n.260+309G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNC3	ENST00000477616.2 link	c.2236G>A	p.Asp746Asn	missense_variant	Exon 4 of 5	1	NM_004977.3	ENSP00000434241.1	Q14003
KCNC3	ENST00000670667.1 link	c.2170+309G>A		intron_variant	Intron 3 of 3			ENSP00000499301.1	A0A590UJ62
KCNC3	ENST00000376959.6 link	c.2170+309G>A		intron_variant	Intron 3 of 4	5		ENSP00000366158.2	E7ETH1
KCNC3	ENST00000474951.1 link	c.118+309G>A		intron_variant	Intron 2 of 3	2		ENSP00000432438.1	E9PQY4

Frequencies

GnomAD3 genomes

AF:

0.0000711

AC:

AN:

126498

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000304

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000129

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000691

AC:

AN:

955624

Hom.:

Cov.:

AF XY:

0.0000604

AC XY:

AN XY:

463698

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000648

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.0000606

Gnomad4 NFE exome

AF:

0.0000596

Gnomad4 OTH exome

AF:

0.000122

GnomAD4 genome

AF:

0.0000790

AC:

AN:

126564

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

59666

show subpopulations

Gnomad4 AFR

AF:

0.0000306

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000304

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000129

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.60

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.23

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.060

REVEL

Uncertain

0.33

Sift

Uncertain

0.024

Sift4G

Benign

0.78

Polyphen

0.77

Vest4

0.27

MVP

0.80

ClinPred

0.15

GERP RS

2.3

Varity_R

0.085

gMVP

0.17

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over