rs73424032

Positions:

chr11-17771771-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001112741.2(KCNC1):c.677A>T(p.Asn226Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

KCNC1
NM_001112741.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.854

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 links:

KCNC1 (HGNC:):

KCNC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNC1. . Gene score misZ 4.5189 (greater than the threshold 3.09). Trascript score misZ 5.1707 (greater than threshold 3.09). GenCC has associacion of gene with progressive myoclonic epilepsy type 7, progressive myoclonus epilepsy, complex neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.037018508).

BP6

Variant 11-17771771-A-T is Benign according to our data. Variant chr11-17771771-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 578014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000243 (37/152358) while in subpopulation AFR AF= 0.000866 (36/41588). AF 95% confidence interval is 0.000643. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC1	NM_001112741.2 linkuse as main transcript	c.677A>T	p.Asn226Ile	missense_variant	2/4	ENST00000265969.8	NP_001106212.1	P48547-2
KCNC1	NM_004976.4 linkuse as main transcript	c.677A>T	p.Asn226Ile	missense_variant	2/2		NP_004967.1	P48547-1
KCNC1	XM_047426916.1 linkuse as main transcript	c.677A>T	p.Asn226Ile	missense_variant	2/4		XP_047282872.1
KCNC1	XR_930866.3 linkuse as main transcript	n.1899A>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC1	ENST00000265969.8 linkuse as main transcript	c.677A>T	p.Asn226Ile	missense_variant	2/4	5	NM_001112741.2	ENSP00000265969.7		P48547-2

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251484

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00125

Gnomad4 AMR exome

AF:

0.0000224

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000243

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000314

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Progressive myoclonic epilepsy type 7

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The KCNC1 p.Asn226Ile variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs73424032) and ClinVar (classified as a VUS by Invitae and as likely benign by Ambry Genetics). The variant was also identified in control databases in 19 of 282884 chromosomes at a frequency of 0.000067 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 17 of 24966 chromosomes (freq: 0.000681), Other in 1 of 7226 chromosomes (freq: 0.000138) and Latino in 1 of 35436 chromosomes (freq: 0.000028), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish) or South Asian populations. The p.Asn226 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.49

T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.037

T;T

MetaSVM

Uncertain

0.0068

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.74

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.20

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.0

B;.

Vest4

0.10

MVP

0.63

MPC

1.7

ClinPred

0.039

GERP RS

0.69

Varity_R

0.087

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over