19-50320579-G-A

Position:

• chr19-50320579-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004977.3(KCNC3):​c.2170+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00786 in 1,608,416 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (15 hom., cov: 29)
  • Exomes 𝑓: 0.0078 (114 hom.)
• Consequence: KCNC3 NM_004977.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0880

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-50320579-G-A is Benign according to our data. Variant chr19-50320579-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 522270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50320579-G-A is described in Lovd as [Benign]. Variant chr19-50320579-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00885 (1344/151910) while in subpopulation NFE AF= 0.00937 (636/67910). AF 95% confidence interval is 0.00876. There are 15 homozygotes in gnomad4. There are 766 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1344 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.2170+14C>T		intron_variant		ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.1942+14C>T		intron_variant			NP_001359234.1
KCNC3	NR_110912.2	n.260+14C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.2170+14C>T		intron_variant		1	NM_004977.3	ENSP00000434241
KCNC3	ENST00000376959.6	c.2170+14C>T		intron_variant		5		ENSP00000366158	A2
KCNC3	ENST00000474951.1	c.118+14C>T		intron_variant		2		ENSP00000432438
KCNC3	ENST00000670667.1	c.2170+14C>T		intron_variant				ENSP00000499301	P3

Frequencies

GnomAD3 genomes AF: 0.00885 AC: 1344 AN: 151794 Hom.: 15 Cov.: 29

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0578

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00936

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00890 AC: 2146 AN: 241046 Hom.: 36 AF XY: 0.00858 AC XY: 1123 AN XY: 130858

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00132

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.0520

Gnomad NFE exome AF: 0.00906

Gnomad OTH exome AF: 0.00626

GnomAD4 exome AF: 0.00776 AC: 11302 AN: 1456506 Hom.: 114 Cov.: 32 AF XY: 0.00758 AC XY: 5492 AN XY: 724316

Gnomad4 AFR exome AF: 0.000629

Gnomad4 AMR exome AF: 0.00149

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.0482

Gnomad4 NFE exome AF: 0.00747

Gnomad4 OTH exome AF: 0.00537

GnomAD4 genome AF: 0.00885 AC: 1344 AN: 151910 Hom.: 15 Cov.: 29 AF XY: 0.0103 AC XY: 766 AN XY: 74242

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0578

Gnomad4 NFE AF: 0.00937

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00466 Hom.: 2

Bravo AF: 0.00429

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2021	- -

Spinocerebellar ataxia type 13 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.0
DANN	Benign	0.51

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: rs189018316; hg19: chr19-50823836;