rs193921123

Variant names:

• chr1-16449174-G-T
• rs193921123
• NM_018090.5:c.462G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018090.5(NECAP2):​c.462G>T​(p.Glu154Asp) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NECAP2 NM_018090.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.827
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3371086).

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.462G>T	p.Glu154Asp	missense	Exon 5 of 8	NP_060560.1	Q9NVZ3-1
	NECAP2	NM_001145277.2		c.462G>T	p.Glu154Asp	missense	Exon 5 of 7	NP_001138749.1	Q9NVZ3-2
	NECAP2	NM_001145278.2		c.384G>T	p.Glu128Asp	missense	Exon 5 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.462G>T	p.Glu154Asp	missense	Exon 5 of 8	ENSP00000338746.5	Q9NVZ3-1
	NECAP2	ENST00000443980.6	TSL:2	c.462G>T	p.Glu154Asp	missense	Exon 5 of 7	ENSP00000391942.2	Q9NVZ3-2
	NECAP2	ENST00000966887.1		c.462G>T	p.Glu154Asp	missense	Exon 5 of 8	ENSP00000636946.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.83
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.19
Sift	Uncertain	0.025	D
Sift4G	Benign	0.085	T
Polyphen		0.12	B
Vest4		0.27
MutPred		0.57		Loss of ubiquitination at K153 (P = 0.0877)
MVP		0.49
MPC		0.37
ClinPred		0.82	D
GERP RS		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.56
Mutation Taster		=62/38	polymorphism

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: rs193921123; hg19: chr1-16775669; COSMIC: COSV61433743; COSMIC: COSV61433743;