chr12-8082298-G-A

Variant names:

• chr12-8082298-G-A
• rs1555168520
• NM_015509.4:c.10G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015509.4(NECAP1):​c.10G>A​(p.Glu4Lys) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E4G) has been classified 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: 6.74
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 21

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284697 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3751549).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015509.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NECAP1	NM_015509.4	MANE Select	c.10G>A	p.Glu4Lys	missense	Exon 1 of 8	NP_056324.2
	NECAP1	NR_024260.2		n.25G>A		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NECAP1	ENST00000339754.11	TSL:1 MANE Select	c.10G>A	p.Glu4Lys	missense	Exon 1 of 8	ENSP00000341737.5	Q8NC96-1
	NECAP1	ENST00000450991.6	TSL:1	n.10G>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000401963.2	Q8NC96-2
	NECAP1	ENST00000639955.1	TSL:5	c.10G>A	p.Glu4Lys	missense	Exon 2 of 9	ENSP00000491067.1	Q8NC96-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 21 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.59
MutPred		0.33		Gain of ubiquitination at E4 (P = 0.0121)
MVP		0.50
MPC		0.71
ClinPred		0.96	D
GERP RS		3.9
PromoterAI		-0.092	Neutral
Varity_R		0.60
gMVP		0.57
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs1555168520; hg19: chr12-8234894;