rs797045633

Variant names:

• chr19-50320351-T-G
• rs797045633
• NM_004977.3:c.2171-2A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_004977.3(KCNC3):​c.2171-2A>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNC3 NM_004977.3 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.632
• Publications: 2 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, MODERATE, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

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.2171-2A>C		splice_acceptor intron	N/A	NP_004968.2
	KCNC3	NM_001372305.1		c.1943-2A>C		splice_acceptor intron	N/A	NP_001359234.1
	KCNC3	NR_110912.2		n.260+242A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.2171-2A>C		splice_acceptor intron	N/A	ENSP00000434241.1	Q14003
	KCNC3	ENST00000670667.1		c.2170+242A>C		intron	N/A	ENSP00000499301.1	A0A590UJ62
	KCNC3	ENST00000376959.6	TSL:5	c.2170+242A>C		intron	N/A	ENSP00000366158.2	E7ETH1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 205270 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 108808

African (AFR) AF: 0.00 AC: 0 AN: 6450

American (AMR) AF: 0.00 AC: 0 AN: 11284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5448

East Asian (EAS) AF: 0.00 AC: 0 AN: 10296

South Asian (SAS) AF: 0.00 AC: 0 AN: 34362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 115984

Other (OTH) AF: 0.00 AC: 0 AN: 10922

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	32
DANN	Benign	0.95
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.48	N
PhyloP100		0.63
GERP RS		2.2
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.68		Position offset: -32
DS_AL_spliceai		0.96		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797045633; hg19: chr19-50823608; COSMIC: COSV65387348;