chr11-17772515-C-A

Variant names:

• chr11-17772515-C-A
• rs1554991422
• NM_001112741.2:c.1421C>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001112741.2(KCNC1):​c.1421C>A​(p.Ser474Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNC1 NM_001112741.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 5 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity KCNC1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC1	NM_001112741.2	c.1421C>A	p.Ser474Tyr	missense_variant	Exon 2 of 4	ENST00000265969.8	NP_001106212.1
KCNC1	NM_004976.4	c.1421C>A	p.Ser474Tyr	missense_variant	Exon 2 of 2		NP_004967.1
KCNC1	XM_047426916.1	c.1421C>A	p.Ser474Tyr	missense_variant	Exon 2 of 4		XP_047282872.1
KCNC1	XR_930866.3	n.2643C>A		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC1	ENST00000265969.8	c.1421C>A	p.Ser474Tyr	missense_variant	Exon 2 of 4	5	NM_001112741.2	ENSP00000265969.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy type 7 Uncertain:1

Mar 09, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNC1-related disease. This sequence change replaces serine with tyrosine at codon 474 of the KCNC1 protein (p.Ser474Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.8	D;D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.014	D;D;.
Polyphen		0.98	D;.;.
Vest4		0.39
MutPred		0.26		Loss of disorder (P = 0.0439);Loss of disorder (P = 0.0439);.;
MVP		0.95
MPC		2.9
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.34
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554991422; hg19: chr11-17794062; COSMIC: COSV56393253; COSMIC: COSV56393253;