19-50323390-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004977.3(KCNC3):c.1563G>A(p.Ala521=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000878 in 1,614,166 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (8 hom.)
• Consequence: KCNC3 NM_004977.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.77

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-50323390-C-T is Benign according to our data. Variant chr19-50323390-C-T is described in ClinVar as [Benign]. Clinvar id is 586081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00462 (703/152326) while in subpopulation AFR AF= 0.0148 (616/41580). AF 95% confidence interval is 0.0138. There are 11 homozygotes in gnomad4. There are 325 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 697 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNC3	NM_004977.3	c.1563G>A	p.Ala521=	synonymous_variant	2/5	ENST00000477616.2
KCNC3	NM_001372305.1	c.1335G>A	p.Ala445=	synonymous_variant	2/5
KCNC3	NR_110912.2	n.69-2606G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNC3	ENST00000477616.2	c.1563G>A	p.Ala521=	synonymous_variant	2/5	1	NM_004977.3
KCNC3	ENST00000670667.1	c.1563G>A	p.Ala521=	synonymous_variant	2/4			P3
KCNC3	ENST00000376959.6	c.1563G>A	p.Ala521=	synonymous_variant	2/5	5		A2
KCNC3	ENST00000474951.1	c.-74-2606G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 697 AN: 152208 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00123 AC: 308 AN: 251358 Hom.: 5 AF XY: 0.00104 AC XY: 142 AN XY: 135916

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000488 AC: 714 AN: 1461840 Hom.: 8 Cov.: 34 AF XY: 0.000465 AC XY: 338 AN XY: 727226

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000869

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.000993

GnomAD4 genome AF: 0.00462 AC: 703 AN: 152326 Hom.: 11 Cov.: 32 AF XY: 0.00436 AC XY: 325 AN XY: 74466

Gnomad4 AFR AF: 0.0148

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00229 Hom.: 2

Bravo AF: 0.00572

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	KCNC3: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	3.1
Dann	Benign	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

LitVar

Other links and lift over

dbSNP: rs116768044; hg19: chr19-50826647;