1-16458891-C-A

Position:

• chr1-16458891-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145277.2(NECAP2):​c.717C>A​(p.Asp239Glu) 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. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NECAP2 NM_001145277.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.32

Genes affected

NECAP2 (HGNC:25528): (NECAP endocytosis associated 2) This gene likely encodes a member of the adaptin-ear-binding coat-associated protein family. Studies of a similar protein in rat suggest a role in clathrin-mediated endocytosis. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2009]

NECAP2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030620694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NECAP2	NM_018090.5	c.*1C>A		3_prime_UTR_variant	8/8	ENST00000337132.10	NP_060560.1
NECAP2	NM_001145277.2	c.717C>A	p.Asp239Glu	missense_variant	7/7		NP_001138749.1
NECAP2	XM_047424713.1	c.558C>A	p.Asp186Glu	missense_variant	7/7		XP_047280669.1
NECAP2	NM_001145278.2	c.*1C>A		3_prime_UTR_variant	8/8		NP_001138750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NECAP2	ENST00000337132.10	c.*1C>A		3_prime_UTR_variant	8/8	1	NM_018090.5	ENSP00000338746.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251432 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2024

The c.717C>A (p.D239E) alteration is located in exon 7 (coding exon 7) of the NECAP2 gene. This alteration results from a C to A substitution at nucleotide position 717, causing the aspartic acid (D) at amino acid position 239 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.8
DANN	Uncertain	0.98
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.037
Sift	Benign	0.058	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.031
MutPred		0.24		Loss of loop (P = 0.0128);
MVP		0.30
MPC		0.30
ClinPred		0.49	T
GERP RS		-3.3
gMVP		0.24

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: rs776170340; hg19: chr1-16785386;