Genetic Variant NM_001112741.2:c.494C>A (chr11-17736496-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001112741.2(KCNC1):c.494C>A(p.Pro165His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P165L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KCNC1
NM_001112741.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Publications

0 publications found

Variant links:

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]

KCNC1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
progressive myoclonic epilepsy type 7
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
progressive myoclonus epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

KCNC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08911294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC1	NM_001112741.2 link	c.494C>A	p.Pro165His	missense_variant	Exon 1 of 4	ENST00000265969.8	NP_001106212.1	P48547-2
KCNC1	NM_004976.4 link	c.494C>A	p.Pro165His	missense_variant	Exon 1 of 2		NP_004967.1	P48547-1
KCNC1	XM_047426916.1 link	c.494C>A	p.Pro165His	missense_variant	Exon 1 of 4		XP_047282872.1
KCNC1	XR_930866.3 link	n.1716C>A		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC1	ENST00000265969.8 link	c.494C>A	p.Pro165His	missense_variant	Exon 1 of 4	5	NM_001112741.2	ENSP00000265969.7		P48547-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1441512

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

716944

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33076

American (AMR)

AF:

0.00

AC:

AN:

43274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25820

East Asian (EAS)

AF:

0.00

AC:

AN:

39248

South Asian (SAS)

AF:

0.00

AC:

AN:

84976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1107438

Other (OTH)

AF:

0.00

AC:

AN:

59750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.82

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.089

T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

0.97

L;L

PhyloP100

1.6

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.71

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.092

T;T

Sift4G

Benign

0.092

T;T

Polyphen

0.075

B;.

Vest4

0.14

MutPred

0.19

Gain of MoRF binding (P = 0.0579);Gain of MoRF binding (P = 0.0579);

MVP

0.51

MPC

1.9

ClinPred

0.15

GERP RS

5.2

Varity_R

0.28

gMVP

0.70

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over