12-8082299-A-G

Position:

• chr12-8082299-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015509.4(NECAP1):​c.11A>G​(p.Glu4Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NECAP1 NM_015509.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.07

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37701106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NECAP1	NM_015509.4	c.11A>G	p.Glu4Gly	missense_variant	1/8	ENST00000339754.11	NP_056324.2
NECAP1	NR_024260.2	n.26A>G		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NECAP1	ENST00000339754.11	c.11A>G	p.Glu4Gly	missense_variant	1/8	1	NM_015509.4	ENSP00000341737.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 21 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2021

This sequence change replaces glutamic acid with glycine at codon 4 of the NECAP1 protein (p.Glu4Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T;T;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.84	.;T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.38	T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	.;N;.;.;.;N
REVEL	Benign	0.17
Sift	Uncertain	0.0020	.;D;.;.;.;D
Sift4G	Uncertain	0.0030	.;D;.;.;.;D
Polyphen		0.98	D;D;.;.;.;.
Vest4		0.50
MutPred		0.30		Gain of catalytic residue at E8 (P = 0.0021);Gain of catalytic residue at E8 (P = 0.0021);Gain of catalytic residue at E8 (P = 0.0021);Gain of catalytic residue at E8 (P = 0.0021);Gain of catalytic residue at E8 (P = 0.0021);Gain of catalytic residue at E8 (P = 0.0021);
MVP		0.57
MPC		0.59
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.54
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-8234895;