rs1555781403

Positions:

• chr19-50323428-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004977.3(KCNC3):​c.1525A>G​(p.Met509Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.1525A>G	p.Met509Val	missense_variant	2/5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.1297A>G	p.Met433Val	missense_variant	2/5		NP_001359234.1
KCNC3	NR_110912.2	n.69-2644A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.1525A>G	p.Met509Val	missense_variant	2/5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.1525A>G	p.Met509Val	missense_variant	2/4			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.1525A>G	p.Met509Val	missense_variant	2/5	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.-74-2644A>G		intron_variant		2		ENSP00000432438.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 28, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.71	.;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.87
Sift	Benign	0.11	T;T
Sift4G	Benign	0.089	T;T
Polyphen		0.58	P;D
Vest4		0.88
MutPred		0.74		Loss of ubiquitination at K512 (P = 0.0505);Loss of ubiquitination at K512 (P = 0.0505);
MVP		0.93
ClinPred		0.89	D
GERP RS		3.3
Varity_R		0.48
gMVP		0.96

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

LitVar

Other links and lift over

dbSNP: rs1555781403; hg19: chr19-50826685;