12-44508983-T-C

Variant names:

• chr12-44508983-T-C
• rs1250914359
• NM_001145108.2:c.2402A>G

Variant summary

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

The NM_001145108.2(NELL2):​c.2402A>G​(p.Asn801Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000158 in 1,459,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NELL2 NM_001145108.2 missense, splice_region
• Scores: Splicing: ADA: 0.7810
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08

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]

ACMG classification

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
NELL2	NM_001145108.2	c.2402A>G	p.Asn801Ser	missense_variant, splice_region_variant	Exon 20 of 20	ENST00000429094.7	NP_001138580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NELL2	ENST00000429094.7	c.2402A>G	p.Asn801Ser	missense_variant, splice_region_variant	Exon 20 of 20	1	NM_001145108.2	ENSP00000390680.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1459856 Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 13 AN XY: 726270

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2552A>G (p.N851S) alteration is located in exon 21 (coding exon 21) of the NELL2 gene. This alteration results from a A to G substitution at nucleotide position 2552, causing the asparagine (N) at amino acid position 851 to be replaced by a serine (S). 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	0.27
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;T;T;.;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;.;D;D;.;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.1	.;M;.;M;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0050	D;D;D;D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D;D;D;D
Polyphen		0.55, 0.68	.;P;P;P;.;.;.
Vest4		0.56
MutPred		0.59		.;Gain of catalytic residue at K800 (P = 0.0012);.;Gain of catalytic residue at K800 (P = 0.0012);.;.;.;
MVP		0.74
MPC		0.20
ClinPred		0.88	D
GERP RS		5.3
Varity_R		0.13
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.78
dbscSNV1_RF	Benign	0.42
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1250914359; hg19: chr12-44902766;