rs201901386

Variant names:

• chr5-139848069-C-A
• rs201901386
• NM_004883.3:c.2401G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-139848069-C-A
• chr5-139848069-C-T

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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
• Publications: 1 publications found

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]

NRG2 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000250692 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01815033).
• BS2: High AC in GnomAd4 at 206 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004883.3. 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
	NRG2	NM_004883.3	MANE Select	c.2401G>T	p.Ala801Ser	missense	Exon 10 of 10	NP_004874.1	O14511-1
	NRG2	NM_013982.3		c.2425G>T	p.Ala809Ser	missense	Exon 11 of 11	NP_053585.1	O14511-3
	NRG2	NM_013983.3		c.2407G>T	p.Ala803Ser	missense	Exon 11 of 11	NP_053586.1	O14511-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG2	ENST00000361474.6	TSL:1 MANE Select	c.2401G>T	p.Ala801Ser	missense	Exon 10 of 10	ENSP00000354910.1	O14511-1
	NRG2	ENST00000358522.7	TSL:1	c.2407G>T	p.Ala803Ser	missense	Exon 11 of 11	ENSP00000351323.3	O14511-4
	NRG2	ENST00000289422.11	TSL:5	c.2425G>T	p.Ala809Ser	missense	Exon 11 of 11	ENSP00000289422.7	O14511-3

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

GnomAD2 exomes AF: 0.00132 AC: 124 AN: 94118 AF XY: 0.00128

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 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

African (AFR) AF: 0.000439 AC: 12 AN: 27312

American (AMR) AF: 0.00123 AC: 38 AN: 30928

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 7 AN: 23952

East Asian (EAS) AF: 0.00 AC: 0 AN: 30592

South Asian (SAS) AF: 0.000799 AC: 60 AN: 75118

European-Finnish (FIN) AF: 0.000360 AC: 13 AN: 36110

Middle Eastern (MID) AF: 0.000489 AC: 2 AN: 4090

European-Non Finnish (NFE) AF: 0.00305 AC: 3238 AN: 1063250

Other (OTH) AF: 0.00291 AC: 163 AN: 56054

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

African (AFR) AF: 0.000409 AC: 17 AN: 41524

American (AMR) AF: 0.00131 AC: 20 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000382 AC: 4 AN: 10478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 67896

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00176 Hom.: 0

Bravo AF: 0.00164

ExAC AF: 0.000692 AC: 17

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	0.066
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.050	N
REVEL	Benign	0.054
Sift	Benign	0.22	T
Sift4G	Benign	0.24	T
Polyphen		0.010	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
Mutation Taster		=100/0	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

dbSNP: rs201901386; hg19: chr5-139227654;