19-50328960-C-G

Variant names:

• chr19-50328960-C-G
• rs185017345
• NM_004977.3:c.123G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004977.3(KCNC3):​c.123G>C​(p.Gln41His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 800,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19324744).

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.123G>C	p.Gln41His	missense	Exon 1 of 5	NP_004968.2
	KCNC3	NM_001372305.1		c.-106G>C		5_prime_UTR	Exon 1 of 5	NP_001359234.1
	KCNC3	NR_110912.2		n.68+4509G>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.123G>C	p.Gln41His	missense	Exon 1 of 5	ENSP00000434241.1	Q14003
	KCNC3	ENST00000670667.1		c.123G>C	p.Gln41His	missense	Exon 1 of 4	ENSP00000499301.1	A0A590UJ62
	KCNC3	ENST00000376959.6	TSL:5	c.123G>C	p.Gln41His	missense	Exon 1 of 5	ENSP00000366158.2	E7ETH1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000125 AC: 1 AN: 800792 Hom.: 0 Cov.: 11 AF XY: 0.00000258 AC XY: 1 AN XY: 387464

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15256

American (AMR) AF: 0.00 AC: 0 AN: 3508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7622

East Asian (EAS) AF: 0.00 AC: 0 AN: 12426

South Asian (SAS) AF: 0.00 AC: 0 AN: 20988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1910

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 697976

Other (OTH) AF: 0.0000338 AC: 1 AN: 29556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.0	N
PhyloP100		1.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.043	D
Polyphen		0.0020	B
Vest4		0.26
MutPred		0.22		Loss of helix (P = 0.0558)
MVP		0.61
ClinPred		0.15	T
GERP RS		1.1
PromoterAI		-0.023	Neutral
Varity_R		0.13
gMVP		0.14
Mutation Taster		=97/3	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: rs185017345; hg19: chr19-50832217;