Variant 1-240493250-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PS1_ModerateBP4_StrongBS2

The NM_022469.4(GREM2):c.226C>G(p.Gln76Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,614,122 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 10 hom. )

Consequence

GREM2
NM_022469.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.77

Variant links:

Genes affected

GREM2 (HGNC:17655): (gremlin 2, DAN family BMP antagonist) This gene encodes a member of the BMP (bone morphogenic protein) antagonist family. Like BMPs, BMP antagonists contain cystine knots and typically form homo- and heterodimers. The CAN (cerberus and dan) subfamily of BMP antagonists, to which this gene belongs, is characterized by a C-terminal cystine knot with an eight-membered ring. The antagonistic effect of the secreted glycosylated protein encoded by this gene is likely due to its direct binding to BMP proteins. As an antagonist of BMP, this gene may play a role in regulating organogenesis, body patterning, and tissue differentiation. [provided by RefSeq, Jul 2008]

GREM2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PS1

Transcript NM_022469.4 (GREM2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

BP4

Computational evidence support a benign effect (MetaRNN=0.06051883).

BS2

High AC in GnomAd4 at 274 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GREM2	NM_022469.4 link	c.226C>G	p.Gln76Glu	missense_variant	2/2	ENST00000318160.5	NP_071914.3
GREM2	XM_047427832.1 link	c.280C>G	p.Gln94Glu	missense_variant	3/3		XP_047283788.1
GREM2	XM_047427839.1 link	c.280C>G	p.Gln94Glu	missense_variant	4/4		XP_047283795.1
GREM2	XM_011544249.3 link	c.226C>G	p.Gln76Glu	missense_variant	3/3		XP_011542551.1	Q9H772

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GREM2	ENST00000318160.5 link	c.226C>G	p.Gln76Glu	missense_variant	2/2	1	NM_022469.4	ENSP00000318650.4		Q9H772

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

273

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00301

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00169

AC:

423

AN:

250576

Hom.:

AF XY:

0.00177

AC XY:

240

AN XY:

135578

show subpopulations

Gnomad AFR exome

AF:

0.000679

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00176

Gnomad FIN exome

AF:

0.000463

Gnomad NFE exome

AF:

0.00263

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00285

AC:

4159

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

2083

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00180

Gnomad4 FIN exome

AF:

0.000712

Gnomad4 NFE exome

AF:

0.00339

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00180

AC:

274

AN:

152322

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000673

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00301

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00286

Hom.:

Bravo

AF:

0.00181

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00166

AC:

202

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tooth agenesis, selective, 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.020

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.30

Sift

Benign

0.13

Sift4G

Benign

0.10

Polyphen

0.44

Vest4

0.91

MVP

0.60

MPC

1.3

ClinPred

0.026

GERP RS

5.0

Varity_R

0.37

gMVP

0.90

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