rs554197864

Positions:

• chr19-50323193-G-A
• chr19-50323193-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_004977.3(KCNC3):​c.1760C>T​(p.Pro587Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000378 in 1,523,210 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P587R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.32

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14485693).
• BP6: Variant 19-50323193-G-A is Benign according to our data. Variant chr19-50323193-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586083.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNC3	NM_004977.3	c.1760C>T	p.Pro587Leu	missense_variant	2/5	ENST00000477616.2
KCNC3	NM_001372305.1	c.1532C>T	p.Pro511Leu	missense_variant	2/5
KCNC3	NR_110912.2	n.69-2409C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNC3	ENST00000477616.2	c.1760C>T	p.Pro587Leu	missense_variant	2/5	1	NM_004977.3
KCNC3	ENST00000670667.1	c.1760C>T	p.Pro587Leu	missense_variant	2/4			P3
KCNC3	ENST00000376959.6	c.1760C>T	p.Pro587Leu	missense_variant	2/5	5		A2
KCNC3	ENST00000474951.1	c.-74-2409C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000133 AC: 18 AN: 135648 Hom.: 0 AF XY: 0.000121 AC XY: 9 AN XY: 74350

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000400 AC: 549 AN: 1370894 Hom.: 0 Cov.: 30 AF XY: 0.000366 AC XY: 248 AN XY: 677006

Gnomad4 AFR exome AF: 0.000224

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000308

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000483

Gnomad4 OTH exome AF: 0.000244

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74478

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000219

ExAC AF: 0.0000312 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	0.64	D
MutationTaster	Benign	0.97	N;N;N;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.75	P;D
Vest4		0.14
MutPred		0.26		Gain of catalytic residue at P587 (P = 0.025);Gain of catalytic residue at P587 (P = 0.025);
MVP		0.67
ClinPred		0.046	T
GERP RS		2.3
Varity_R		0.091
gMVP		0.55

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: rs554197864; hg19: chr19-50826450;