rs149036367

chr12-8090250-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_015509.4(NECAP1):c.252G>A(p.Thr84=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: NECAP1 NM_015509.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.895

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 12-8090250-G-A is Benign according to our data. Variant chr12-8090250-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 541853.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.895 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NECAP1	NM_015509.4	c.252G>A	p.Thr84=	synonymous_variant	3/8	ENST00000339754.11
NECAP1	NR_024260.2	n.267G>A		non_coding_transcript_exon_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NECAP1	ENST00000339754.11	c.252G>A	p.Thr84=	synonymous_variant	3/8	1	NM_015509.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251480 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135914

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.0000619 AC XY: 45 AN XY: 727242

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74304

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000174

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 21 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	9.6
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs149036367; hg19: chr12-8242846;