12-44522167-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001145108.2(NELL2):​c.2008G>A​(p.Val670Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,612,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

NELL2
NM_001145108.2 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.13
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.40341148).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NELL2NM_001145108.2 linkc.2008G>A p.Val670Ile missense_variant Exon 18 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.2008G>A p.Val670Ile missense_variant Exon 18 of 20 1 NM_001145108.2 ENSP00000390680.2 Q99435-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152002
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000822
AC:
12
AN:
1460256
Hom.:
0
Cov.:
31
AF XY:
0.00000964
AC XY:
7
AN XY:
726442
show subpopulations
Gnomad4 AFR exome
AF:
0.0000599
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000816
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152002
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74218
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 26, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2158G>A (p.V720I) alteration is located in exon 19 (coding exon 19) of the NELL2 gene. This alteration results from a G to A substitution at nucleotide position 2158, causing the valine (V) at amino acid position 720 to be replaced by an isoleucine (I). 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
0.089
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.041
.;T;T;T;.;.;.
Eigen
Uncertain
0.21
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.86
D;.;D;D;.;D;D
M_CAP
Benign
0.053
D
MetaRNN
Benign
0.40
T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.16
T
MutationAssessor
Benign
0.63
.;N;.;N;.;.;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.17
N;N;N;N;N;N;N
REVEL
Uncertain
0.49
Sift
Benign
1.0
T;T;T;T;T;T;T
Sift4G
Benign
0.46
T;T;T;T;T;T;T
Polyphen
1.0
.;D;D;D;.;.;.
Vest4
0.54
MutPred
0.48
.;Gain of catalytic residue at M675 (P = 0);.;Gain of catalytic residue at M675 (P = 0);.;.;.;
MVP
0.45
MPC
0.58
ClinPred
0.83
D
GERP RS
5.6
Varity_R
0.086
gMVP
0.17

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: rs747987094; hg19: chr12-44915950; COSMIC: COSV61575958; COSMIC: COSV61575958; API