chr3-51712611-G-C

Variant names:

• chr3-51712611-G-C
• NM_000839.5:c.589G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000839.5(GRM2):​c.589G>C​(p.Glu197Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GRM2 NM_000839.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

GRM2 (HGNC:4594): (glutamate metabotropic receptor 2) L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000839.5. 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
	GRM2	NM_000839.5	MANE Select	c.589G>C	p.Glu197Gln	missense	Exon 3 of 6	NP_000830.2	Q14416
	GRM2	NM_001349117.2		c.-761G>C		5_prime_UTR	Exon 3 of 7	NP_001336046.1
	GRM2	NM_001349116.2		c.-138-408G>C		intron	N/A	NP_001336045.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM2	ENST00000395052.8	TSL:2 MANE Select	c.589G>C	p.Glu197Gln	missense	Exon 3 of 6	ENSP00000378492.3	Q14416
	GRM2	ENST00000296479.9	TSL:1	n.589G>C		non_coding_transcript_exon	Exon 3 of 7	ENSP00000296479.5	H7BXL3
	GRM2	ENST00000464585.1	TSL:1	n.2268G>C		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727190

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

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	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.3	L
PhyloP100		10
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.72		Gain of MoRF binding (P = 0.0534)
MVP		0.79
MPC		1.5
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.74
gMVP		0.70
Mutation Taster		=37/63	disease causing

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

hg19: chr3-51746627;