rs111744086

Positions:

• chr19-50323024-G-A

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.1929C>T​(p.Gly643Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,545,834 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (26 hom., cov: 32)
  • Exomes 𝑓: 0.010 (105 hom.)
• Consequence: KCNC3 NM_004977.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.84

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=-0.62).
• BP6: Variant 19-50323024-G-A is Benign according to our data. Variant chr19-50323024-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 288184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50323024-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0142 (2155/152246) while in subpopulation AFR AF= 0.0236 (979/41564). AF 95% confidence interval is 0.0223. There are 26 homozygotes in gnomad4. There are 1013 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2155 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.1929C>T	p.Gly643Gly	synonymous_variant	2/5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.1701C>T	p.Gly567Gly	synonymous_variant	2/5		NP_001359234.1
KCNC3	NR_110912.2	n.69-2240C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.1929C>T	p.Gly643Gly	synonymous_variant	2/5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.1929C>T	p.Gly643Gly	synonymous_variant	2/4			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.1929C>T	p.Gly643Gly	synonymous_variant	2/5	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.-74-2240C>T		intron_variant		2		ENSP00000432438.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2150 AN: 152128 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00566

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00953 AC: 1358 AN: 142518 Hom.: 16 AF XY: 0.00937 AC XY: 720 AN XY: 76846

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.00838

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00345

Gnomad FIN exome AF: 0.00860

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0105 AC: 14593 AN: 1393588 Hom.: 105 Cov.: 33 AF XY: 0.0102 AC XY: 7002 AN XY: 687196

Gnomad4 AFR exome AF: 0.0230

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.00843

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00313

Gnomad4 FIN exome AF: 0.00806

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.0142 AC: 2155 AN: 152246 Hom.: 26 Cov.: 32 AF XY: 0.0136 AC XY: 1013 AN XY: 74452

Gnomad4 AFR AF: 0.0236

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.00566

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0123 Hom.: 9

Bravo AF: 0.0155

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Spinocerebellar ataxia type 13 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.6
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs111744086; hg19: chr19-50826281; COSMIC: COSV65387044;