12-44520094-T-C

Position:

• chr12-44520094-T-C

Variant summary

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

The NM_001145108.2(NELL2):​c.2311A>G​(p.Lys771Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 5.10

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/exons	MANE	Protein	UniProt
NELL2	NM_001145108.2	c.2311A>G	p.Lys771Glu	missense_variant	19/20	ENST00000429094.7	NP_001138580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NELL2	ENST00000429094.7	c.2311A>G	p.Lys771Glu	missense_variant	19/20	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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2023

The c.2461A>G (p.K821E) alteration is located in exon 20 (coding exon 20) of the NELL2 gene. This alteration results from a A to G substitution at nucleotide position 2461, causing the lysine (K) at amino acid position 821 to be replaced by a glutamic acid (E). 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	0.15
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T;T;T;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T;.;T;T;.;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.1	.;M;.;M;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.084	T;T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T
Polyphen		1.0, 1.0	.;D;D;D;.;.;.
Vest4		0.72
MutPred		0.48		.;Gain of catalytic residue at L774 (P = 0);.;Gain of catalytic residue at L774 (P = 0);.;.;.;
MVP		0.41
MPC		0.78
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.36
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-44913877;