1-240493459-G-C

Variant names:

• chr1-240493459-G-C
• rs1333951923
• NM_022469.4:c.17C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_022469.4(GREM2):​c.17C>G​(p.Ser6Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,607,810 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GREM2 NM_022469.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• tooth agenesis, selective, 9

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.2306 (below the threshold of 3.09). Trascript score misZ: 0.5294 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.19084278).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022469.4. 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
	GREM2	NM_022469.4	MANE Select	c.17C>G	p.Ser6Cys	missense	Exon 2 of 2	NP_071914.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM2	ENST00000318160.5	TSL:1 MANE Select	c.17C>G	p.Ser6Cys	missense	Exon 2 of 2	ENSP00000318650.4	Q9H772
	GREM2	ENST00000859904.1		c.17C>G	p.Ser6Cys	missense	Exon 3 of 3	ENSP00000529963.1
	GREM2	ENST00000859905.1		c.17C>G	p.Ser6Cys	missense	Exon 2 of 2	ENSP00000529964.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.00000206 AC: 3 AN: 1455584 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723448

African (AFR) AF: 0.0000599 AC: 2 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25758

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.00 AC: 0 AN: 85486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108662

Other (OTH) AF: 0.00 AC: 0 AN: 60128

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000121 AC: 5 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000417739), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

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	0.068
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.063
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.032
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.85	P
Vest4		0.20
MVP		0.63
MPC		1.0
ClinPred		0.39	T
GERP RS		3.3
Varity_R		0.12
gMVP		0.62
Mutation Taster		=78/22	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: rs1333951923; hg19: chr1-240656759;