19-50320284-C-T

Variant names:

• chr19-50320284-C-T
• rs958323371
• NM_004977.3:c.2236G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_004977.3(KCNC3):​c.2236G>A​(p.Asp746Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 16)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41
• Publications: 1 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23249534).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000079 (10/126564) while in subpopulation NFE AF = 0.000129 (8/62188). AF 95% confidence interval is 0.0000631. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 16. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.2236G>A	p.Asp746Asn	missense_variant	Exon 4 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.2008G>A	p.Asp670Asn	missense_variant	Exon 4 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.260+309G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.2236G>A	p.Asp746Asn	missense_variant	Exon 4 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.2170+309G>A		intron_variant	Intron 3 of 3			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.2170+309G>A		intron_variant	Intron 3 of 4	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.118+309G>A		intron_variant	Intron 2 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes AF: 0.0000711 AC: 9 AN: 126498 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000304

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000129

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000534 AC: 3 AN: 56130 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000136

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000691 AC: 66 AN: 955624 Hom.: 0 Cov.: 13 AF XY: 0.0000604 AC XY: 28 AN XY: 463698

African (AFR) AF: 0.00 AC: 0 AN: 22490

American (AMR) AF: 0.00 AC: 0 AN: 15952

Ashkenazi Jewish (ASJ) AF: 0.000648 AC: 10 AN: 15424

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30118

South Asian (SAS) AF: 0.0000252 AC: 1 AN: 39612

European-Finnish (FIN) AF: 0.0000606 AC: 2 AN: 33014

Middle Eastern (MID) AF: 0.000664 AC: 2 AN: 3014

European-Non Finnish (NFE) AF: 0.0000596 AC: 45 AN: 754932

Other (OTH) AF: 0.000122 AC: 5 AN: 41068

GnomAD4 genome AF: 0.0000790 AC: 10 AN: 126564 Hom.: 0 Cov.: 16 AF XY: 0.000101 AC XY: 6 AN XY: 59666

African (AFR) AF: 0.0000306 AC: 1 AN: 32728

American (AMR) AF: 0.00 AC: 0 AN: 10778

Ashkenazi Jewish (ASJ) AF: 0.000304 AC: 1 AN: 3288

East Asian (EAS) AF: 0.00 AC: 0 AN: 4182

South Asian (SAS) AF: 0.00 AC: 0 AN: 3720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 228

European-Non Finnish (NFE) AF: 0.000129 AC: 8 AN: 62188

Other (OTH) AF: 0.00 AC: 0 AN: 1746

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNC3: PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.0	N
PhyloP100		3.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.060	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.024	D
Sift4G	Benign	0.78	T
Polyphen		0.77	P
Vest4		0.27
MVP		0.80
ClinPred		0.15	T
GERP RS		2.3
Varity_R		0.085
gMVP		0.17
Mutation Taster		=95/5	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: rs958323371; hg19: chr19-50823541;