chr12-8082381-C-T

Variant names:

• chr12-8082381-C-T
• rs2120448200
• NM_015509.4:c.93C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PP3_Moderate BP6_Moderate

The NM_015509.4(NECAP1):​c.93C>T​(p.Tyr31Tyr) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NECAP1 NM_015509.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.02
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 12-8082381-C-T is Benign according to our data. Variant chr12-8082381-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1663057.Status of the report is criteria_provided_single_submitter, 1 stars.

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.93C>T	p.Tyr31Tyr	splice_region synonymous	Exon 1 of 8	NP_056324.2
	NECAP1	NR_024260.2		n.108C>T		splice_region 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.93C>T	p.Tyr31Tyr	splice_region synonymous	Exon 1 of 8	ENSP00000341737.5	Q8NC96-1
	NECAP1	ENST00000450991.6	TSL:1	n.93C>T		splice_region non_coding_transcript_exon	Exon 1 of 7	ENSP00000401963.2	Q8NC96-2
	NECAP1	ENST00000639955.1	TSL:5	c.93C>T	p.Tyr31Tyr	splice_region synonymous	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: Likely benign

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
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		4.0
PromoterAI		-0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.010		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: rs2120448200; hg19: chr12-8234977;