dbSNP rs757288037: NELL2:p.Arg629Pro (chr12-44523403-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001145108.2(NELL2):c.1886G>C(p.Arg629Pro) variant causes a missense change. 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. R629Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NELL2
NM_001145108.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.08

Publications

1 publications found

Variant links:

Genes affected

NELL2 (HGNC:7751): (neural EGFL like 2) The protein encoded by this gene is a glycoprotein containing several von Willebrand factor C domains and epidermal growth factor (EGF)-like domains. The encoded protein acts as a homotrimer and is found in the cytoplasm. Several variants encoding a few different isoforms exist, and at least one isoform appears to be a secreted protein. Studies in mouse suggest that this protein plays a role in neural cell growth and differentiation as well as in oncogenesis. [provided by RefSeq, Feb 2009]

NELL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.785

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NELL2	NM_001145108.2	MANE Select	c.1886G>C	p.Arg629Pro	missense	Exon 17 of 20	NP_001138580.1	Q99435-1
NELL2	NM_001145107.2		c.2036G>C	p.Arg679Pro	missense	Exon 18 of 21	NP_001138579.1	Q99435-3
NELL2	NM_001145110.2		c.1955G>C	p.Arg652Pro	missense	Exon 18 of 21	NP_001138582.1	Q99435-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NELL2	ENST00000429094.7	TSL:1 MANE Select	c.1886G>C	p.Arg629Pro	missense	Exon 17 of 20	ENSP00000390680.2	Q99435-1
NELL2	ENST00000452445.6	TSL:1	c.1886G>C	p.Arg629Pro	missense	Exon 18 of 21	ENSP00000394612.2	Q99435-1
NELL2	ENST00000395487.6	TSL:1	c.1883G>C	p.Arg628Pro	missense	Exon 17 of 20	ENSP00000378866.2	Q99435-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251472

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

0.12

PhyloP100

6.1

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.67

Sift

Benign

0.085

Sift4G

Benign

0.29

Polyphen

1.0

Vest4

0.86

MutPred

0.56

Gain of catalytic residue at R629 (P = 0)

MVP

0.79

MPC

0.77

ClinPred

0.90

GERP RS

4.9

Varity_R

0.83

gMVP

0.94

Mutation Taster

=6/94

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over