rs137964265

Positions:

chr12-8090249-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000339754.11(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 (★★). Synonymous variant affecting the same amino acid position (i.e. T84T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 2 hom. )

Consequence

NECAP1
ENST00000339754.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.23

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]

NECAP1 links:

Genome browser will be placed here

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 linkuse as main transcript	c.251C>T	p.Thr84Met	missense_variant	3/8	ENST00000339754.11	NP_056324.2
NECAP1	NR_024260.2 linkuse as main transcript	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 linkuse as main transcript	c.251C>T	p.Thr84Met	missense_variant	3/8	1	NM_015509.4	ENSP00000341737	P4	Q8NC96-1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251468

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000267

AC:

391

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

192

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000306

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000263

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000390

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.20

T;T;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

.;D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.25

T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

2.0

M;M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.6

.;D;.;.;N

REVEL

Benign

0.22

Sift

Uncertain

0.0080

.;D;.;.;D

Sift4G

Uncertain

0.023

.;D;.;.;D

Polyphen

1.0

D;D;.;.;.

Vest4

0.76

MVP

0.67

MPC

1.4

ClinPred

0.27

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.63

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

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