1-16440811-A-G

Position:

• chr1-16440811-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018090.5(NECAP2):​c.50A>G​(p.His17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,862 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H17L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NECAP2 NM_018090.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41194797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NECAP2	NM_018090.5	c.50A>G	p.His17Arg	missense_variant	1/8	ENST00000337132.10	NP_060560.1
NECAP2	NM_001145277.2	c.50A>G	p.His17Arg	missense_variant	1/7		NP_001138749.1
NECAP2	XM_047424715.1	c.50A>G	p.His17Arg	missense_variant	1/7		XP_047280671.1
NECAP2	NM_001145278.2	c.14+36A>G		intron_variant			NP_001138750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NECAP2	ENST00000337132.10	c.50A>G	p.His17Arg	missense_variant	1/8	1	NM_018090.5	ENSP00000338746.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 21, 2022

The c.50A>G (p.H17R) alteration is located in exon 1 (coding exon 1) of the NECAP2 gene. This alteration results from a A to G substitution at nucleotide position 50, causing the histidine (H) at amino acid position 17 to be replaced by an arginine (R). 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
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.78	.;T;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.8	M;.;M
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.24
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.74	P;.;P
Vest4		0.67
MutPred		0.53		Gain of MoRF binding (P = 0.0087);Gain of MoRF binding (P = 0.0087);Gain of MoRF binding (P = 0.0087);
MVP		0.54
MPC		0.95
ClinPred		0.60	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.73
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs2086678716; hg19: chr1-16767306;