19-50328960-C-A

Position:

• chr19-50328960-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000477616.2(KCNC3):​c.123G>T​(p.Gln41His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 947,006 control chromosomes in the GnomAD database, including 566 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.039 (394 hom., cov: 24)
  • Exomes 𝑓: 0.0033 (172 hom.)
• Consequence: KCNC3 ENST00000477616.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.85

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013549328).
• BP6: Variant 19-50328960-C-A is Benign according to our data. Variant chr19-50328960-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 284725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50328960-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.123G>T	p.Gln41His	missense_variant	1/5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.-106G>T		5_prime_UTR_variant	1/5		NP_001359234.1
KCNC3	NR_110912.2	n.68+4509G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.123G>T	p.Gln41His	missense_variant	1/5	1	NM_004977.3	ENSP00000434241
KCNC3	ENST00000670667.1	c.123G>T	p.Gln41His	missense_variant	1/4			ENSP00000499301	P3
KCNC3	ENST00000376959.6	c.123G>T	p.Gln41His	missense_variant	1/5	5		ENSP00000366158	A2
KCNC3	ENST00000474951.1	c.-75+4509G>T		intron_variant		2		ENSP00000432438

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5692 AN: 146148 Hom.: 392 Cov.: 24

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.000885

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0200

GnomAD3 exomes AF: 0.0345 AC: 2 AN: 58 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 32

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00326 AC: 2610 AN: 800764 Hom.: 172 Cov.: 11 AF XY: 0.00299 AC XY: 1159 AN XY: 387448

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.00118

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000191

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000158

Gnomad4 OTH exome AF: 0.00873

GnomAD4 genome AF: 0.0390 AC: 5706 AN: 146242 Hom.: 394 Cov.: 24 AF XY: 0.0373 AC XY: 2659 AN XY: 71212

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.000885

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0198

Alfa AF: 0.0300 Hom.: 27

Bravo AF: 0.0431

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.46	T;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.0	.;N
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.67	N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.043	D;D
Polyphen		0.0020	.;B
Vest4		0.26
MutPred		0.22		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
ClinPred		0.058	T
GERP RS		1.1
Varity_R		0.13
gMVP		0.14

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

Other links and lift over

dbSNP: rs185017345; hg19: chr19-50832217;