chr19-50328314-G-T

Position:

• chr19-50328314-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000477616.2(KCNC3):​c.769C>A​(p.Pro257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 1,128,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: KCNC3 ENST00000477616.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.50

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18358856).
• BS2: High AC in GnomAdExome4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.769C>A	p.Pro257Thr	missense_variant	1/5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.541C>A	p.Pro181Thr	missense_variant	1/5		NP_001359234.1
KCNC3	NR_110912.2	n.68+5155C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.769C>A	p.Pro257Thr	missense_variant	1/5	1	NM_004977.3	ENSP00000434241
KCNC3	ENST00000670667.1	c.769C>A	p.Pro257Thr	missense_variant	1/4			ENSP00000499301	P3
KCNC3	ENST00000376959.6	c.769C>A	p.Pro257Thr	missense_variant	1/5	5		ENSP00000366158	A2
KCNC3	ENST00000474951.1	c.-75+5155C>A		intron_variant		2		ENSP00000432438

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148060 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000469 AC: 46 AN: 980002 Hom.: 0 Cov.: 33 AF XY: 0.0000474 AC XY: 22 AN XY: 464486

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: 0.0000524

Gnomad4 OTH exome AF: 0.0000276

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148060 Hom.: 0 Cov.: 30 AF XY: 0.0000139 AC XY: 1 AN XY: 72092

Gnomad4 AFR AF: 0.0000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 06, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNC3 protein function. ClinVar contains an entry for this variant (Variation ID: 521572). This missense change has been observed in individual(s) with clinical features of spinocerebellar ataxia (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 257 of the KCNC3 protein (p.Pro257Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.66	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.81	.;L
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.75	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.38	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.0060	.;B
Vest4		0.18
MutPred		0.25		Gain of phosphorylation at P257 (P = 0.0108);Gain of phosphorylation at P257 (P = 0.0108);
MVP		0.75
ClinPred		0.076	T
GERP RS		0.95
Varity_R		0.13
gMVP		0.15

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: rs1232558368; hg19: chr19-50831571;