1-16443673-G-T

Variant names:

• chr1-16443673-G-T
• rs755393819
• NM_018090.5:c.134G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018090.5(NECAP2):​c.134G>T​(p.Arg45Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R45W) 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: 8.95
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

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.134G>T	p.Arg45Leu	missense	Exon 2 of 8	NP_060560.1	Q9NVZ3-1
	NECAP2	NM_001145277.2		c.134G>T	p.Arg45Leu	missense	Exon 2 of 7	NP_001138749.1	Q9NVZ3-2
	NECAP2	NM_001145278.2		c.56G>T	p.Arg19Leu	missense	Exon 2 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.134G>T	p.Arg45Leu	missense	Exon 2 of 8	ENSP00000338746.5	Q9NVZ3-1
	NECAP2	ENST00000443980.6	TSL:2	c.134G>T	p.Arg45Leu	missense	Exon 2 of 7	ENSP00000391942.2	Q9NVZ3-2
	NECAP2	ENST00000966887.1		c.134G>T	p.Arg45Leu	missense	Exon 2 of 8	ENSP00000636946.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.024	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.78		Loss of MoRF binding (P = 0.0355)
MVP		0.85
MPC		1.2
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.90
Mutation Taster		=44/56	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: rs755393819; hg19: chr1-16770168;