12-44520074-C-G

Variant names:

• chr12-44520074-C-G
• NM_001145108.2:c.2331G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145108.2(NELL2):​c.2331G>C​(p.Met777Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M777T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NELL2 NM_001145108.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21099043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NELL2	NM_001145108.2	c.2331G>C	p.Met777Ile	missense_variant	Exon 19 of 20	ENST00000429094.7	NP_001138580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NELL2	ENST00000429094.7	c.2331G>C	p.Met777Ile	missense_variant	Exon 19 of 20	1	NM_001145108.2	ENSP00000390680.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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.2481G>C (p.M827I) alteration is located in exon 20 (coding exon 20) of the NELL2 gene. This alteration results from a G to C substitution at nucleotide position 2481, causing the methionine (M) at amino acid position 827 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	0.11
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.096	.;T;T;T;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.83	T;.;T;T;.;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	.;L;.;L;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.89	N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.38	T;T;T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T;T;T
Polyphen		0.029, 0.050	.;B;B;B;.;.;.
Vest4		0.29
MutPred		0.38		.;Gain of catalytic residue at L774 (P = 0);.;Gain of catalytic residue at L774 (P = 0);.;.;.;
MVP		0.17
MPC		0.17
ClinPred		0.47	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-44913857;