19-50320324-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_004977.3(KCNC3):c.2196C>T(p.Pro732=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P732P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 17)
  • Exomes 𝑓: 0.00072 (2 hom.)
• Consequence: KCNC3 NM_004977.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.692

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 19-50320324-G-A is Benign according to our data. Variant chr19-50320324-G-A is described in ClinVar as [Benign]. Clinvar id is 2650318.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.692 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00305 (396/129712) while in subpopulation AFR AF= 0.0104 (364/34952). AF 95% confidence interval is 0.00953. There are 1 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 17. This position pass quality control queck.
• BS2: High AC in GnomAd at 395 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNC3	NM_004977.3	c.2196C>T	p.Pro732=	synonymous_variant	4/5	ENST00000477616.2
KCNC3	NM_001372305.1	c.1968C>T	p.Pro656=	synonymous_variant	4/5
KCNC3	NR_110912.2	n.260+269C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNC3	ENST00000477616.2	c.2196C>T	p.Pro732=	synonymous_variant	4/5	1	NM_004977.3
KCNC3	ENST00000376959.6	c.2170+269C>T		intron_variant		5		A2
KCNC3	ENST00000474951.1	c.118+269C>T		intron_variant		2
KCNC3	ENST00000670667.1	c.2170+269C>T		intron_variant				P3

Frequencies

GnomAD3 genomes AF: 0.00305 AC: 395 AN: 129610 Hom.: 1 Cov.: 17

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00224

GnomAD3 exomes AF: 0.00145 AC: 78 AN: 53844 Hom.: 0 AF XY: 0.00135 AC XY: 37 AN XY: 27416

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.00107

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: 0.000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000718 AC: 218 AN: 303490 Hom.: 2 Cov.: 4 AF XY: 0.000603 AC XY: 95 AN XY: 157512

Gnomad4 AFR exome AF: 0.0179

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000693

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00305 AC: 396 AN: 129712 Hom.: 1 Cov.: 17 AF XY: 0.00275 AC XY: 171 AN XY: 62118

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.00152

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00221

Alfa AF: 0.000188 Hom.: 0

Bravo AF: 0.00394

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

KCNC3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	8.4
Dann	Benign	0.74

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: rs375488867; hg19: chr19-50823581;