rs114192110

chr19-50323969-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.984G>A(p.Pro328=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000766 in 1,613,462 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (9 hom.)
• Consequence: KCNC3 NM_004977.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.62

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=-0.77).
• BP6: Variant 19-50323969-C-T is Benign according to our data. Variant chr19-50323969-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 586085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50323969-C-T is described in Lovd as [Likely_benign]. Variant chr19-50323969-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.62 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00409 (623/152248) while in subpopulation AFR AF= 0.0142 (592/41554). AF 95% confidence interval is 0.0133. There are 10 homozygotes in gnomad4. There are 311 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 622 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNC3	NM_004977.3	c.984G>A	p.Pro328=	synonymous_variant	2/5	ENST00000477616.2
KCNC3	NM_001372305.1	c.756G>A	p.Pro252=	synonymous_variant	2/5
KCNC3	NR_110912.2	n.69-3185G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNC3	ENST00000477616.2	c.984G>A	p.Pro328=	synonymous_variant	2/5	1	NM_004977.3
KCNC3	ENST00000670667.1	c.984G>A	p.Pro328=	synonymous_variant	2/4			P3
KCNC3	ENST00000376959.6	c.984G>A	p.Pro328=	synonymous_variant	2/5	5		A2
KCNC3	ENST00000474951.1	c.-74-3185G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 622 AN: 152130 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00107 AC: 268 AN: 251030 Hom.: 1 AF XY: 0.000803 AC XY: 109 AN XY: 135712

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000420 AC: 613 AN: 1461214 Hom.: 9 Cov.: 34 AF XY: 0.000378 AC XY: 275 AN XY: 726728

Gnomad4 AFR exome AF: 0.0150

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00409 AC: 623 AN: 152248 Hom.: 10 Cov.: 32 AF XY: 0.00418 AC XY: 311 AN XY: 74424

Gnomad4 AFR AF: 0.0142

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.00436

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2022	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Spinocerebellar ataxia type 13 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.29
Dann	Benign	0.64

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: rs114192110; hg19: chr19-50827226; COSMIC: COSV65388735;