chr19-50322999-C-T

Variant names:

• chr19-50322999-C-T
• rs1555781339
• NM_004977.3:c.1954G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004977.3(KCNC3):​c.1954G>A​(p.Glu652Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,397,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4029869).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC3	NM_004977.3	MANE Select	c.1954G>A	p.Glu652Lys	missense	Exon 2 of 5	NP_004968.2
	KCNC3	NM_001372305.1		c.1726G>A	p.Glu576Lys	missense	Exon 2 of 5	NP_001359234.1
	KCNC3	NR_110912.2		n.69-2215G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.1954G>A	p.Glu652Lys	missense	Exon 2 of 5	ENSP00000434241.1
	KCNC3	ENST00000670667.1		c.1954G>A	p.Glu652Lys	missense	Exon 2 of 4	ENSP00000499301.1
	KCNC3	ENST00000376959.6	TSL:5	c.1954G>A	p.Glu652Lys	missense	Exon 2 of 5	ENSP00000366158.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397994 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 689622

African (AFR) AF: 0.00 AC: 0 AN: 31624

American (AMR) AF: 0.00 AC: 0 AN: 35876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25158

East Asian (EAS) AF: 0.00 AC: 0 AN: 35818

South Asian (SAS) AF: 0.00 AC: 0 AN: 79208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4966

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1079308

Other (OTH) AF: 0.00 AC: 0 AN: 57912

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 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
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.9	L
PhyloP100		4.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.13	T
Polyphen		0.98	D
Vest4		0.40
MutPred		0.28		Gain of ubiquitination at E652 (P = 0.001)
MVP		0.85
ClinPred		0.85	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.64
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555781339; hg19: chr19-50826256;