19-50323013-G-C

Variant names:

• chr19-50323013-G-C
• NM_004977.3:c.1940C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004977.3(KCNC3):​c.1940C>G​(p.Pro647Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,298 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.1940C>G	p.Pro647Arg	missense_variant	Exon 2 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.1712C>G	p.Pro571Arg	missense_variant	Exon 2 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.69-2229C>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.1940C>G	p.Pro647Arg	missense_variant	Exon 2 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.1940C>G	p.Pro647Arg	missense_variant	Exon 2 of 4			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.1940C>G	p.Pro647Arg	missense_variant	Exon 2 of 5	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.-74-2229C>G		intron_variant	Intron 1 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396298 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 688670

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.0	.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.051	T;D
Sift4G	Benign	0.090	T;T
Polyphen		1.0	D;D
Vest4		0.42
MutPred		0.14		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.87
ClinPred		0.96	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.63

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50826270;