1-16458847-C-T

Variant names:

• chr1-16458847-C-T
• rs199917711
• NM_018090.5:c.749C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018090.5(NECAP2):​c.749C>T​(p.Thr250Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. T250N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: NECAP2 NM_018090.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 0 publications found

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]

CROCCP3 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10613647).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018090.5. 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
	NECAP2	NM_018090.5	MANE Select	c.749C>T	p.Thr250Ile	missense	Exon 8 of 8	NP_060560.1	Q9NVZ3-1
	NECAP2	NM_001145277.2		c.673C>T	p.Leu225Phe	missense	Exon 7 of 7	NP_001138749.1	Q9NVZ3-2
	NECAP2	NM_001145278.2		c.671C>T	p.Thr224Ile	missense	Exon 8 of 8	NP_001138750.1	Q9NVZ3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NECAP2	ENST00000337132.10	TSL:1 MANE Select	c.749C>T	p.Thr250Ile	missense	Exon 8 of 8	ENSP00000338746.5	Q9NVZ3-1
	NECAP2	ENST00000443980.6	TSL:2	c.673C>T	p.Leu225Phe	missense	Exon 7 of 7	ENSP00000391942.2	Q9NVZ3-2
	NECAP2	ENST00000966887.1		c.746C>T	p.Thr249Ile	missense	Exon 8 of 8	ENSP00000636946.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461288 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726970

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111814

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.075
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.12
Sift	Benign	0.039	D
Sift4G	Benign	0.79	T
Polyphen		0.53	P
Vest4		0.074
MVP		0.37
MPC		0.44
ClinPred		0.67	D
GERP RS		5.9
Varity_R		0.077
gMVP		0.19
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs199917711; hg19: chr1-16785342;