4-112514971-G-T

Variant names:

• chr4-112514971-G-T
• rs1736397904
• NM_024019.4:c.505C>A

Variant summary

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

The NM_024019.4(NEUROG2):​c.505C>A​(p.Arg169Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NEUROG2 NM_024019.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

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]

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 rank	MANE	Protein	UniProt
NEUROG2	NM_024019.4	c.505C>A	p.Arg169Ser	missense_variant	Exon 2 of 2	ENST00000313341.4	NP_076924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEUROG2	ENST00000313341.4	c.505C>A	p.Arg169Ser	missense_variant	Exon 2 of 2	1	NM_024019.4	ENSP00000317333.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461262 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726976

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.505C>A (p.R169S) alteration is located in exon 2 (coding exon 1) of the NEUROG2 gene. This alteration results from a C to A substitution at nucleotide position 505, causing the arginine (R) at amino acid position 169 to be replaced by a serine (S). 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.49		Gain of glycosylation at R169 (P = 0.0854);
MVP		0.95
MPC		1.8
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.66
gMVP		0.96

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

Other links and lift over

dbSNP: rs1736397904; hg19: chr4-113436127;