19-50322999-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.1954G>A	p.Glu652Lys	missense_variant	Exon 2 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.1726G>A	p.Glu576Lys	missense_variant	Exon 2 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.69-2215G>A		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.1954G>A	p.Glu652Lys	missense_variant	Exon 2 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.1954G>A	p.Glu652Lys	missense_variant	Exon 2 of 4			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.1954G>A	p.Glu652Lys	missense_variant	Exon 2 of 5	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.-74-2215G>A		intron_variant	Intron 1 of 3	2		ENSP00000432438.1

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

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.9	.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.98	D;D
Vest4		0.40
MutPred		0.28		Gain of ubiquitination at E652 (P = 0.001);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555781339; hg19: chr19-50826256;