5-139848069-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004883.3(NRG2):c.2401G>T(p.Ala801Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,499,318 control chromosomes in the GnomAD database, including 6 homozygotes. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0026 (6 hom.)
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

Genes affected

NRG2 (HGNC:7998): (neuregulin 2) This gene encodes a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ERBB family of receptors, this protein induces the growth and differentiation of epithelial, neuronal, glial, and other types of cells. The gene consists of 12 exons and the genomic structure is similar to that of neuregulin 1, another member of the neuregulin family of ligands. The products of these genes mediate distinct biological processes by acting at different sites in tissues and eliciting different biological responses in cells. This gene is located close to the region for demyelinating Charcot-Marie-Tooth disease locus, but is not responsible for this disease. Alternative transcript variants encoding distinct isoforms have been described. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01815033).
• BS2: High Homozygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG2	NM_004883.3	c.2401G>T	p.Ala801Ser	missense_variant	10/10	ENST00000361474.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG2	ENST00000361474.6	c.2401G>T	p.Ala801Ser	missense_variant	10/10	1	NM_004883.3	A2

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 206 AN: 151804 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000382

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00132 AC: 124 AN: 94118 Hom.: 2 AF XY: 0.00128 AC XY: 68 AN XY: 53050

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000687

Gnomad ASJ exome AF: 0.000722

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000822

Gnomad FIN exome AF: 0.000152

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00262 AC: 3533 AN: 1347406 Hom.: 6 Cov.: 33 AF XY: 0.00253 AC XY: 1680 AN XY: 664616

Gnomad4 AFR exome AF: 0.000439

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.000292

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000799

Gnomad4 FIN exome AF: 0.000360

Gnomad4 NFE exome AF: 0.00305

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.00136 AC: 206 AN: 151912 Hom.: 0 Cov.: 29 AF XY: 0.00133 AC XY: 99 AN XY: 74248

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000382

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00164

ExAC AF: 0.000692 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.2425G>T (p.A809S) alteration is located in exon 11 (coding exon 11) of the NRG2 gene. This alteration results from a G to T substitution at nucleotide position 2425, causing the alanine (A) at amino acid position 809 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	Benign	0.066
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Benign	0.91
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T;T;T;T;T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.018	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.050	N;N;N;N;N;N
REVEL	Benign	0.054
Sift	Benign	0.22	T;T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;T
Polyphen		0.010, 0.022, 0.018, 0.37	.;B;B;.;B;B
Vest4		0.059
MVP		0.39
MPC		0.74
ClinPred		0.024	T
GERP RS		1.4
Varity_R		0.094
gMVP		0.33

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: rs201901386; hg19: chr5-139227654;