chr12-44520074-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 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
• 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 0 ACMG points.

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

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.2331G>C	p.Met777Ile	missense	Exon 19 of 20	NP_001138580.1	Q99435-1
	NELL2	NM_001145107.2		c.2481G>C	p.Met827Ile	missense	Exon 20 of 21	NP_001138579.1	Q99435-3
	NELL2	NM_001145110.2		c.2400G>C	p.Met800Ile	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.2331G>C	p.Met777Ile	missense	Exon 19 of 20	ENSP00000390680.2	Q99435-1
	NELL2	ENST00000452445.6	TSL:1	c.2331G>C	p.Met777Ile	missense	Exon 20 of 21	ENSP00000394612.2	Q99435-1
	NELL2	ENST00000395487.6	TSL:1	c.2328G>C	p.Met776Ile	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	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
Eigen	Benign	-0.14
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.17
Sift	Benign	0.38	T
Sift4G	Benign	0.38	T
Polyphen		0.029	B
Vest4		0.29
MutPred		0.38		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
Mutation Taster		=94/6	polymorphism

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: chr12-44913857;