rs766170364

Variant names:

• chr3-51712625-C-G
• rs766170364
• NM_000839.5:c.603C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-51712625-C-G
• chr3-51712625-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001349117.2(GRM2):​c.-747C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GRM2 NM_001349117.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.313872).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349117.2. 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.603C>G	p.Phe201Leu	missense	Exon 3 of 6	NP_000830.2	Q14416
	GRM2	NM_001349117.2		c.-747C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 7	NP_001336046.1
	GRM2	NM_001349117.2		c.-747C>G		5_prime_UTR	Exon 3 of 7	NP_001336046.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM2	ENST00000395052.8	TSL:2 MANE Select	c.603C>G	p.Phe201Leu	missense	Exon 3 of 6	ENSP00000378492.3	Q14416
	GRM2	ENST00000296479.9	TSL:1	n.603C>G		non_coding_transcript_exon	Exon 3 of 7	ENSP00000296479.5	H7BXL3
	GRM2	ENST00000464585.1	TSL:1	n.2282C>G		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251354 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461790 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 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: 53336

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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	Pathogenic	0.79
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.37
Sift	Benign	0.65	T
Sift4G	Benign	0.66	T
Polyphen		0.0090	B
Vest4		0.57
MutPred		0.62		Loss of helix (P = 0.1706)
MVP		0.82
MPC		1.0
ClinPred		0.12	T
GERP RS		3.2
Varity_R		0.44
gMVP		0.40
Mutation Taster		=42/58	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

dbSNP: rs766170364; hg19: chr3-51746641;