rs1555169422

Variant names:

• chr12-8095639-A-T
• rs1555169422
• NM_015509.4:c.715A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015509.4(NECAP1):​c.715A>T​(p.Thr239Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. T239T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NECAP1 NM_015509.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.704
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037483275).

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.715A>T	p.Thr239Ser	missense	Exon 7 of 8	NP_056324.2
	NECAP1	NR_024260.2		n.648A>T		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NECAP1	ENST00000339754.11	TSL:1 MANE Select	c.715A>T	p.Thr239Ser	missense	Exon 7 of 8	ENSP00000341737.5	Q8NC96-1
	NECAP1	ENST00000450991.6	TSL:1	n.*324A>T		non_coding_transcript_exon	Exon 6 of 7	ENSP00000401963.2	Q8NC96-2
	NECAP1	ENST00000450991.6	TSL:1	n.*324A>T		3_prime_UTR	Exon 6 of 7	ENSP00000401963.2	Q8NC96-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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	Benign	0.071
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.5
DANN	Benign	0.34
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.70
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.026
Sift	Benign	1.0	T
Sift4G	Benign	0.94	T
Polyphen		0.018	B
Vest4		0.13
MutPred		0.26		Gain of catalytic residue at A241 (P = 0.0877)
MVP		0.23
MPC		0.44
ClinPred		0.028	T
GERP RS		0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.024
gMVP		0.12
Mutation Taster		=96/4	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: rs1555169422; hg19: chr12-8248235;