1-240493367-C-G

Variant names:

• chr1-240493367-C-G
• rs533988435
• NM_022469.4:c.109G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS2_Supporting

The NM_022469.4(GREM2):​c.109G>C​(p.Gly37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G37S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: GREM2 NM_022469.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• Publications: 1 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 -2 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). GenCC associations: The gene is linked to tooth agenesis, selective, 9.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0942395).
• BS2: High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.109G>C	p.Gly37Arg	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.109G>C	p.Gly37Arg	missense	Exon 2 of 2	ENSP00000318650.4	Q9H772
	GREM2	ENST00000859904.1		c.109G>C	p.Gly37Arg	missense	Exon 3 of 3	ENSP00000529963.1
	GREM2	ENST00000859905.1		c.109G>C	p.Gly37Arg	missense	Exon 2 of 2	ENSP00000529964.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.016
Sift	Benign	0.25	T
Sift4G	Benign	0.44	T
Polyphen		0.16	B
Vest4		0.074
MutPred		0.24		Gain of solvent accessibility (P = 0.019)
MVP		0.42
MPC		1.2
ClinPred		0.13	T
GERP RS		1.8
Varity_R		0.053
gMVP		0.82
Mutation Taster		=76/24	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: rs533988435; hg19: chr1-240656667;