12-8082314-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015509.4(NECAP1):ā€‹c.26C>Gā€‹(p.Ser9Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000329 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 32)

Consequence

NECAP1
NM_015509.4 missense

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.74
Variant links:
Genes affected
NECAP1 (HGNC:24539): (NECAP endocytosis associated 1) This gene encodes a protein containing two characteristic WXXF motifs. The encoded protein localizes to clathrin-coated vesicles, where it binds components of the adapter protein complexes and aids in endocytosis. Loss of function of this gene results in early infantile epileptic encephalopathy-21. There is a pseudogene for this gene on chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NECAP1NM_015509.4 linkuse as main transcriptc.26C>G p.Ser9Cys missense_variant 1/8 ENST00000339754.11
NECAP1NR_024260.2 linkuse as main transcriptn.41C>G non_coding_transcript_exon_variant 1/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NECAP1ENST00000339754.11 linkuse as main transcriptc.26C>G p.Ser9Cys missense_variant 1/81 NM_015509.4 P4Q8NC96-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00000796
AC:
2
AN:
251264
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135834
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
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
Cov.:
30
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
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:
0.0000712
Hom.:
0
Bravo
AF:
0.0000491
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 21 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 21, 2022This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 9 of the NECAP1 protein (p.Ser9Cys). This variant is present in population databases (rs374673959, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with NECAP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Benign
0.0023
T
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Benign
0.34
T;T;.;.;.;.
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Benign
0.59
D
LIST_S2
Pathogenic
0.98
.;D;D;D;D;D
M_CAP
Benign
0.059
D
MetaRNN
Uncertain
0.72
D;D;D;D;D;D
MetaSVM
Benign
-0.36
T
MutationAssessor
Pathogenic
3.2
M;M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-4.5
.;D;.;.;.;D
REVEL
Uncertain
0.33
Sift
Uncertain
0.0010
.;D;.;.;.;T
Sift4G
Uncertain
0.0080
.;D;.;.;.;T
Polyphen
1.0
D;D;.;.;.;.
Vest4
0.80
MVP
0.78
MPC
1.4
ClinPred
0.99
D
GERP RS
3.9
Varity_R
0.69
gMVP
0.67

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.

Other links and lift over

dbSNP: rs374673959; hg19: chr12-8234910; API