2-232891456-C-G

Variant names:

• chr2-232891456-C-G
• NM_019850.3:c.1174G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_019850.3(NGEF):​c.1174G>C​(p.Ala392Pro) 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A392T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NGEF NM_019850.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.579

Genes affected

NGEF (HGNC:7807): (neuronal guanine nucleotide exchange factor) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in several processes, including activation of GTPase activity; ephrin receptor signaling pathway; and negative regulation of dendritic spine morphogenesis. Predicted to be located in cytosol. Predicted to be active in glutamatergic synapse. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28166038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGEF	NM_019850.3	c.1174G>C	p.Ala392Pro	missense_variant	Exon 8 of 15	ENST00000264051.8	NP_062824.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGEF	ENST00000264051.8	c.1174G>C	p.Ala392Pro	missense_variant	Exon 8 of 15	1	NM_019850.3	ENSP00000264051.3
NGEF	ENST00000373552.8	c.898G>C	p.Ala300Pro	missense_variant	Exon 6 of 13	2		ENSP00000362653.4
NGEF	ENST00000416114.3	c.343G>C	p.Ala115Pro	missense_variant	Exon 4 of 6	3		ENSP00000401063.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.058	T;T;T
Sift4G	Benign	0.10	T;T;.
Polyphen		0.99	D;.;.
Vest4		0.43
MutPred		0.32		Gain of disorder (P = 0.1673);.;.;
MVP		0.54
MPC		1.7
ClinPred		0.36	T
GERP RS		-0.61
Varity_R		0.24
gMVP		0.58

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: chr2-233756166;