chr12-8082314-C-T

Variant names:

• chr12-8082314-C-T
• rs374673959
• NM_015509.4:c.26C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015509.4(NECAP1):​c.26C>T​(p.Ser9Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,552 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S9C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NECAP1 NM_015509.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.74

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]

ENSG00000284697 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NECAP1	NM_015509.4	c.26C>T	p.Ser9Phe	missense_variant	Exon 1 of 8	ENST00000339754.11	NP_056324.2
NECAP1	NR_024260.2	n.41C>T		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NECAP1	ENST00000339754.11	c.26C>T	p.Ser9Phe	missense_variant	Exon 1 of 8	1	NM_015509.4	ENSP00000341737.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460552 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726354

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.53	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.2	M;M;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.4	.;D;.;.;.;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	.;D;.;.;.;T
Sift4G	Uncertain	0.0090	.;D;.;.;.;T
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.91
MutPred		0.57		Gain of catalytic residue at K14 (P = 0.0025);Gain of catalytic residue at K14 (P = 0.0025);Gain of catalytic residue at K14 (P = 0.0025);Gain of catalytic residue at K14 (P = 0.0025);Gain of catalytic residue at K14 (P = 0.0025);Gain of catalytic residue at K14 (P = 0.0025);
MVP		0.72
MPC		1.3
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.85
gMVP		0.71

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: rs374673959; hg19: chr12-8234910; COSMIC: COSV60249371; COSMIC: COSV60249371;