chr12-8096053-A-G

Position:

• chr12-8096053-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015509.4(NECAP1):​c.791A>G​(p.Asn264Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N264D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: NECAP1 NM_015509.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011983514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NECAP1	NM_015509.4	c.791A>G	p.Asn264Ser	missense_variant	8/8	ENST00000339754.11
NECAP1	NR_024260.2	n.724A>G		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NECAP1	ENST00000339754.11	c.791A>G	p.Asn264Ser	missense_variant	8/8	1	NM_015509.4	P4

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000915 AC: 23 AN: 251444 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135902

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461850 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727222

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74472

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000525 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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 22, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 264 of the NECAP1 protein (p.Asn264Ser). This variant is present in population databases (rs145154841, gnomAD 0.06%). 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: 475009). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	0.050
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.28
DEOGEN2	Benign	0.0097	T;T;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.36	N;N;.;.
MutationTaster	Benign	0.89	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.76	.;N;.;.
REVEL	Benign	0.093
Sift	Benign	0.78	.;T;.;.
Sift4G	Benign	1.0	.;T;.;.
Polyphen		0.0020	B;B;.;.
Vest4		0.12
MVP		0.26
MPC		0.39
ClinPred		0.0072	T
GERP RS		2.4
Varity_R		0.021
gMVP		0.15

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

Other links and lift over

dbSNP: rs145154841; hg19: chr12-8248649;