rs35578310

Positions:

• chr19-50323549-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 ENST00000477616.2(KCNC3):​c.1404C>T​(p.Tyr468=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,614,240 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (5 hom.)
• Consequence: KCNC3 ENST00000477616.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.19

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=-0.58).
• BP6: Variant 19-50323549-G-A is Benign according to our data. Variant chr19-50323549-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 586080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50323549-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0027 (412/152360) while in subpopulation AFR AF= 0.00716 (298/41592). AF 95% confidence interval is 0.0065. There are 2 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 412 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.1404C>T	p.Tyr468=	synonymous_variant	2/5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.1176C>T	p.Tyr392=	synonymous_variant	2/5		NP_001359234.1
KCNC3	NR_110912.2	n.69-2765C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.1404C>T	p.Tyr468=	synonymous_variant	2/5	1	NM_004977.3	ENSP00000434241
KCNC3	ENST00000670667.1	c.1404C>T	p.Tyr468=	synonymous_variant	2/4			ENSP00000499301	P3
KCNC3	ENST00000376959.6	c.1404C>T	p.Tyr468=	synonymous_variant	2/5	5		ENSP00000366158	A2
KCNC3	ENST00000474951.1	c.-74-2765C>T		intron_variant		2		ENSP00000432438

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152240 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00719

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00144 AC: 362 AN: 251410 Hom.: 2 AF XY: 0.00123 AC XY: 167 AN XY: 135910

Gnomad AFR exome AF: 0.00831

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000729 AC: 1065 AN: 1461880 Hom.: 5 Cov.: 34 AF XY: 0.000718 AC XY: 522 AN XY: 727242

Gnomad4 AFR exome AF: 0.00863

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0186

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00270 AC: 412 AN: 152360 Hom.: 2 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74494

Gnomad4 AFR AF: 0.00716

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00151 Hom.: 4

Bravo AF: 0.00309

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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 13, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 04, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	KCNC3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.4
DANN	Benign	0.67

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: rs35578310; hg19: chr19-50826806; COSMIC: COSV65386632;