chr1-16451923-C-T

Variant names:

• chr1-16451923-C-T
• rs375487117
• NM_018090.5:c.575C>T

Variant summary

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

The NM_018090.5(NECAP2):​c.575C>T​(p.Pro192Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P192R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NECAP2 NM_018090.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.90
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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.575C>T	p.Pro192Leu	missense	Exon 6 of 8	NP_060560.1	Q9NVZ3-1
	NECAP2	NM_001145277.2		c.575C>T	p.Pro192Leu	missense	Exon 6 of 7	NP_001138749.1	Q9NVZ3-2
	NECAP2	NM_001145278.2		c.497C>T	p.Pro166Leu	missense	Exon 6 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.575C>T	p.Pro192Leu	missense	Exon 6 of 8	ENSP00000338746.5	Q9NVZ3-1
	NECAP2	ENST00000443980.6	TSL:2	c.575C>T	p.Pro192Leu	missense	Exon 6 of 7	ENSP00000391942.2	Q9NVZ3-2
	NECAP2	ENST00000966887.1		c.575C>T	p.Pro192Leu	missense	Exon 6 of 8	ENSP00000636946.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.9
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-8.7	D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.65
MutPred		0.22		Loss of glycosylation at P192 (P = 0.0071)
MVP		0.75
MPC		0.71
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.62
gMVP		0.61
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs375487117; hg19: chr1-16778418;