12-44523403-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145108.2(NELL2):​c.1886G>A​(p.Arg629Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

NELL2
NM_001145108.2 missense

Scores

3
9
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.08
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NELL2NM_001145108.2 linkc.1886G>A p.Arg629Gln missense_variant Exon 17 of 20 ENST00000429094.7 NP_001138580.1 Q99435-1A0A024R0X1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NELL2ENST00000429094.7 linkc.1886G>A p.Arg629Gln missense_variant Exon 17 of 20 1 NM_001145108.2 ENSP00000390680.2 Q99435-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251472
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461836
Hom.:
0
Cov.:
30
AF XY:
0.0000399
AC XY:
29
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000396
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 17, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2036G>A (p.R679Q) alteration is located in exon 18 (coding exon 18) of the NELL2 gene. This alteration results from a G to A substitution at nucleotide position 2036, causing the arginine (R) at amino acid position 679 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.19
.;T;T;T;.;.;.
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
D;.;D;D;.;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.63
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.36
D
MutationAssessor
Benign
0.030
.;N;.;N;.;.;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.77
N;N;N;N;N;N;N
REVEL
Uncertain
0.55
Sift
Benign
0.077
T;T;T;T;T;T;T
Sift4G
Benign
0.57
T;T;T;T;T;T;T
Polyphen
1.0
.;D;D;D;.;.;.
Vest4
0.70
MutPred
0.51
.;Gain of catalytic residue at K634 (P = 0.0015);.;Gain of catalytic residue at K634 (P = 0.0015);.;.;.;
MVP
0.69
MPC
0.63
ClinPred
0.84
D
GERP RS
4.9
Varity_R
0.34
gMVP
0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs757288037; hg19: chr12-44917186; API