12-44523393-A-C

Position:

• chr12-44523393-A-C

Variant summary

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

The ENST00000429094.7(NELL2):​c.1896T>G​(p.His632Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 ENST00000429094.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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.1896T>G	p.His632Gln	missense_variant	17/20	ENST00000429094.7	NP_001138580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NELL2	ENST00000429094.7	c.1896T>G	p.His632Gln	missense_variant	17/20	1	NM_001145108.2	ENSP00000390680	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Oct 25, 2022

The c.2046T>G (p.H682Q) alteration is located in exon 18 (coding exon 18) of the NELL2 gene. This alteration results from a T to G substitution at nucleotide position 2046, causing the histidine (H) at amino acid position 682 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	0.31
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	.;T;T;T;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T;.;T;T;.;T;T
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.59	.;N;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.43	T;T;T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T;T
Polyphen		1.0, 1.0	.;D;D;D;.;.;.
Vest4		0.62
MutPred		0.51		.;Gain of catalytic residue at K634 (P = 0.0198);.;Gain of catalytic residue at K634 (P = 0.0198);.;.;.;
MVP		0.66
MPC		0.59
ClinPred		0.83	D
GERP RS		-2.4
Varity_R		0.12
gMVP		0.53

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: chr12-44917176;