chr1-110211801-G-A

Position:

• chr1-110211801-G-A

Variant summary

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

The ENST00000438661.3(KCNC4):​c.302G>A​(p.Gly101Asp) variant causes a missense change. 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: KCNC4 ENST00000438661.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18

Genes affected

KCNC4 (HGNC:6236): (potassium voltage-gated channel subfamily C member 4) 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 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. It generates atypical voltage-dependent transient current that may be important for neuronal excitability. Multiple transcript variants have been found for this gene. [provided by RefSeq, Jul 2010]

KCNC4 (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, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC4	NM_001039574.3	c.302G>A	p.Gly101Asp	missense_variant	1/4	ENST00000438661.3	NP_001034663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC4	ENST00000438661.3	c.302G>A	p.Gly101Asp	missense_variant	1/4	1	NM_001039574.3	ENSP00000393655.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Ambry Genetics

May 18, 2022

The c.302G>A (p.G101D) alteration is located in exon 1 (coding exon 1) of the KCNC4 gene. This alteration results from a G to A substitution at nucleotide position 302, causing the glycine (G) at amino acid position 101 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.64	N;.;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.032	D;D;D
Sift4G	Uncertain	0.044	D;D;D
Polyphen		0.93	P;.;P
Vest4		0.72
MutPred		0.46		Loss of catalytic residue at V102 (P = 0.0407);Loss of catalytic residue at V102 (P = 0.0407);Loss of catalytic residue at V102 (P = 0.0407);
MVP		0.96
MPC		2.5
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.62
gMVP		0.95

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: chr1-110754423;