chr12-44520015-C-T

Variant names:

• chr12-44520015-C-T
• NM_001145108.2:c.2390G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001145108.2(NELL2):​c.2390G>A​(p.Cys797Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 7.71
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NELL2	NM_001145108.2	MANE Select	c.2390G>A	p.Cys797Tyr	missense	Exon 19 of 20	NP_001138580.1	Q99435-1
	NELL2	NM_001145107.2		c.2540G>A	p.Cys847Tyr	missense	Exon 20 of 21	NP_001138579.1	Q99435-3
	NELL2	NM_001145110.2		c.2459G>A	p.Cys820Tyr	missense	Exon 20 of 21	NP_001138582.1	Q99435-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NELL2	ENST00000429094.7	TSL:1 MANE Select	c.2390G>A	p.Cys797Tyr	missense	Exon 19 of 20	ENSP00000390680.2	Q99435-1
	NELL2	ENST00000452445.6	TSL:1	c.2390G>A	p.Cys797Tyr	missense	Exon 20 of 21	ENSP00000394612.2	Q99435-1
	NELL2	ENST00000395487.6	TSL:1	c.2387G>A	p.Cys796Tyr	missense	Exon 19 of 20	ENSP00000378866.2	Q99435-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.49		Gain of catalytic residue at E793 (P = 0.0012)
MVP		0.78
MPC		0.86
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.99
Mutation Taster		=7/93	disease causing

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

Other links and lift over

hg19: chr12-44913798;