Genetic Variant NEUROG2:p.Arg53Pro (chr4-112515318-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_024019.4(NEUROG2):c.158G>C(p.Arg53Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000017 in 1,415,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

NEUROG2
NM_024019.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.38

Variant links:

Genes affected

NEUROG2 (HGNC:13805): (neurogenin 2) This gene encodes a neural-specific basic helix-loop-helix (bHLH) transcription factor that can specify a neuronal fate on ectodermal cells and is expressed in neural progenitor cells within the developing central and peripheral nervous systems. The protein product of this gene also plays a role in the differentiation and survival of midbrain dopaminergic neurons. [provided by RefSeq, Apr 2012]

NEUROG2 links:

NEUROG2-AS1 (HGNC:40656): (NEUROG2 and ZGRF1 antisense RNA 1)

NEUROG2-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23159039).

BP6

Variant 4-112515318-C-G is Benign according to our data. Variant chr4-112515318-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3195516.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEUROG2	NM_024019.4 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 2	ENST00000313341.4	NP_076924.1	Q9H2A3
NEUROG2-AS1	NR_161159.1 link	n.-61C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEUROG2	ENST00000313341.4 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 2	1	NM_024019.4	ENSP00000317333.3	Q9H2A3
NEUROG2-AS1	ENST00000504009.1 link	n.-113C>G		upstream_gene_variant		3
NEUROG2-AS1	ENST00000506057.1 link	n.-67C>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151826

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1263788

Hom.:

Cov.:

AF XY:

0.0000161

AC XY:

AN XY:

620776

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000224

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151826

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74166

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 27, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Benign

5.3

DANN

Benign

0.29

DEOGEN2

Benign

0.23

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.33

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.79

REVEL

Benign

0.25

Sift

Benign

0.25

Sift4G

Benign

0.29

Polyphen

0.92

Vest4

0.056

MutPred

0.25

Gain of loop (P = 0.0097);

MVP

0.63

MPC

0.96

ClinPred

0.95

GERP RS

0.57

Varity_R

0.096

gMVP

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over