rs137964265
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_015509.4(NECAP1):c.251C>T(p.Thr84Met) variant causes a missense change. The variant allele was found at a frequency of 0.000267 in 1,614,126 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 2 hom. )
Consequence
NECAP1
NM_015509.4 missense
NM_015509.4 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 4.23
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 Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.25288802).
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NECAP1 | NM_015509.4 | c.251C>T | p.Thr84Met | missense_variant | 3/8 | ENST00000339754.11 | NP_056324.2 | |
NECAP1 | NR_024260.2 | n.266C>T | non_coding_transcript_exon_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NECAP1 | ENST00000339754.11 | c.251C>T | p.Thr84Met | missense_variant | 3/8 | 1 | NM_015509.4 | ENSP00000341737.5 |
Frequencies
GnomAD3 genomes AF: 0.000263 AC: 40AN: 152122Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000155 AC: 39AN: 251468Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135910
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GnomAD4 exome AF: 0.000267 AC: 391AN: 1461886Hom.: 2 Cov.: 30 AF XY: 0.000264 AC XY: 192AN XY: 727244
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GnomAD4 genome AF: 0.000263 AC: 40AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74430
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2021 | The c.251C>T (p.T84M) alteration is located in exon 3 (coding exon 3) of the NECAP1 gene. This alteration results from a C to T substitution at nucleotide position 251, causing the threonine (T) at amino acid position 84 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2022 | - - |
Developmental and epileptic encephalopathy, 21 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 84 of the NECAP1 protein (p.Thr84Met). This variant is present in population databases (rs137964265, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NECAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 475005). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
M;M;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;.;.;N
REVEL
Benign
Sift
Uncertain
.;D;.;.;D
Sift4G
Uncertain
.;D;.;.;D
Polyphen
D;D;.;.;.
Vest4
0.76
MVP
0.67
MPC
1.4
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at