chr19-50320579-G-A

Variant names:

• chr19-50320579-G-A
• rs189018316
• NM_004977.3:c.2170+14C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

KCNC3 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 13

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 522270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1344 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004977.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC3	NM_004977.3	MANE Select	c.2170+14C>T		intron	N/A	NP_004968.2
	KCNC3	NM_001372305.1		c.1942+14C>T		intron	N/A	NP_001359234.1
	KCNC3	NR_110912.2		n.260+14C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.2170+14C>T		intron	N/A	ENSP00000434241.1	Q14003
	KCNC3	ENST00000670667.1		c.2170+14C>T		intron	N/A	ENSP00000499301.1	A0A590UJ62
	KCNC3	ENST00000376959.6	TSL:5	c.2170+14C>T		intron	N/A	ENSP00000366158.2	E7ETH1

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

GnomAD2 exomes AF: 0.00890 AC: 2146 AN: 241046 AF XY: 0.00858

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 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

African (AFR) AF: 0.000629 AC: 21 AN: 33382

American (AMR) AF: 0.00149 AC: 66 AN: 44154

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85612

European-Finnish (FIN) AF: 0.0482 AC: 2553 AN: 52984

Middle Eastern (MID) AF: 0.000450 AC: 2 AN: 4444

European-Non Finnish (NFE) AF: 0.00747 AC: 8295 AN: 1110148

Other (OTH) AF: 0.00537 AC: 323 AN: 60126

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

African (AFR) AF: 0.00113 AC: 47 AN: 41430

American (AMR) AF: 0.00235 AC: 36 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.0578 AC: 612 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00937 AC: 636 AN: 67910

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00466 Hom.: 2

Bravo AF: 0.00429

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Spinocerebellar ataxia type 13 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.0
DANN	Benign	0.51
PhyloP100		0.088
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs189018316; hg19: chr19-50823836;