19-50320232-AG-A

Variant names:

• chr19-50320232-AG-A
• rs759727454
• NM_004977.3:c.*13delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004977.3(KCNC3):​c.*13delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (4 hom., cov: 15)
  • Exomes 𝑓: 0.0030 (3 hom.)
• Consequence: KCNC3 NM_004977.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.422
• Publications: 0 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: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 19-50320232-AG-A is Benign according to our data. Variant chr19-50320232-AG-A is described in ClinVar as [Likely_benign]. Clinvar id is 1698028.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0151 (417/27650) while in subpopulation AFR AF = 0.0483 (335/6936). AF 95% confidence interval is 0.044. There are 4 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 15. This position passed quality control check.
• BS2: High AC in GnomAd4 at 417 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.*13delC		3_prime_UTR_variant	Exon 4 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.*13delC		3_prime_UTR_variant	Exon 4 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.260+360delC		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.*13delC		3_prime_UTR_variant	Exon 4 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.2170+360delC		intron_variant	Intron 3 of 3			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.2170+360delC		intron_variant	Intron 3 of 4	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.118+360delC		intron_variant	Intron 2 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 416 AN: 27644 Hom.: 4 Cov.: 15

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00404

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.0123

GnomAD2 exomes AF: 0.00258 AC: 65 AN: 25174 AF XY: 0.00203

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.000324

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.00305 AC: 399 AN: 130994 Hom.: 3 Cov.: 7 AF XY: 0.00294 AC XY: 194 AN XY: 66002

African (AFR) AF: 0.0397 AC: 164 AN: 4128

American (AMR) AF: 0.00207 AC: 10 AN: 4840

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 139 AN: 3110

East Asian (EAS) AF: 0.00 AC: 0 AN: 7564

South Asian (SAS) AF: 0.00 AC: 0 AN: 8430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 732

European-Non Finnish (NFE) AF: 0.000422 AC: 37 AN: 87642

Other (OTH) AF: 0.00727 AC: 49 AN: 6744

GnomAD4 genome AF: 0.0151 AC: 417 AN: 27650 Hom.: 4 Cov.: 15 AF XY: 0.0140 AC XY: 180 AN XY: 12814

African (AFR) AF: 0.0483 AC: 335 AN: 6936

American (AMR) AF: 0.00404 AC: 9 AN: 2226

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 56 AN: 852

East Asian (EAS) AF: 0.00 AC: 0 AN: 914

South Asian (SAS) AF: 0.00 AC: 0 AN: 640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 44

European-Non Finnish (NFE) AF: 0.000853 AC: 12 AN: 14072

Other (OTH) AF: 0.0122 AC: 5 AN: 410

Alfa AF: 0.00430 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 19, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
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: rs759727454; hg19: chr19-50823489;