11-17736093-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001112741.2(KCNC1):c.91G>C(p.Gly31Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G31S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNC1 NM_001112741.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.91

Genes affected

KCNC1 (HGNC:6233): (potassium voltage-gated channel subfamily C member 1) This gene encodes a member of a family of integral membrane proteins that mediate the voltage-dependent potassium ion permeability of excitable membranes. Alternative splicing is thought to result in two transcript variants encoding isoforms that differ at their C-termini. These isoforms have had conflicting names in the literature: the longer isoform has been called both "b" and "alpha", while the shorter isoform has been called both "a" and "beta" (PMIDs 1432046, 12091563). [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNC1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNC1	NM_001112741.2	c.91G>C	p.Gly31Arg	missense_variant	1/4	ENST00000265969.8
KCNC1	NM_004976.4	c.91G>C	p.Gly31Arg	missense_variant	1/2
KCNC1	XM_047426916.1	c.91G>C	p.Gly31Arg	missense_variant	1/4
KCNC1	XR_930866.3	n.1313G>C		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNC1	ENST00000265969.8	c.91G>C	p.Gly31Arg	missense_variant	1/4	5	NM_001112741.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455782 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723686

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: 0.00000270

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 28, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.073	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.67
Sift	Benign	0.30	T;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;.
Vest4		0.69
MutPred		0.56		Gain of MoRF binding (P = 0.0166);Gain of MoRF binding (P = 0.0166);
MVP		0.91
MPC		2.9
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.65
gMVP		0.97

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: chr11-17757640;