5-178994769-T-C

Variant names:

• chr5-178994769-T-C
• rs2645329
• NM_000843.4:c.176A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000843.4(GRM6):​c.176A>G​(p.Gln59Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 1,223,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. Q59P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: GRM6 NM_000843.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.195
• Publications: 22 publications found

Genes affected

GRM6 (HGNC:4598): (glutamate metabotropic receptor 6) 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. Mutations in this gene result in congenital stationary night blindness type 1B. [provided by RefSeq, May 2018]

GRM6 Gene-Disease associations (from GenCC):

• congenital stationary night blindness 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• GRM6-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0795427).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000843.4. 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
	GRM6	NM_000843.4	MANE Select	c.176A>G	p.Gln59Arg	missense	Exon 2 of 11	NP_000834.2	O15303

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM6	ENST00000517717.3	TSL:5 MANE Select	c.176A>G	p.Gln59Arg	missense	Exon 2 of 11	ENSP00000430767.1	O15303
	GRM6	ENST00000231188.9	TSL:2	c.176A>G	p.Gln59Arg	missense	Exon 1 of 10	ENSP00000231188.5	O15303
	GRM6	ENST00000650031.1		c.176A>G	p.Gln59Arg	missense	Exon 3 of 12	ENSP00000497110.1	O15303

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000148 AC: 1 AN: 67784 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000832

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: 0.00000163 AC: 2 AN: 1223376 Hom.: 0 Cov.: 41 AF XY: 0.00000166 AC XY: 1 AN XY: 601392

African (AFR) AF: 0.00 AC: 0 AN: 25210

American (AMR) AF: 0.0000449 AC: 1 AN: 22258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20312

East Asian (EAS) AF: 0.00 AC: 0 AN: 25538

South Asian (SAS) AF: 0.0000168 AC: 1 AN: 59674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3490

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 989316

Other (OTH) AF: 0.00 AC: 0 AN: 48682

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 17041

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.73	N
PhyloP100		-0.20
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.065
Sift	Benign	0.57	T
Sift4G	Benign	0.53	T
Polyphen		0.0040	B
Vest4		0.046
MutPred		0.28		Gain of MoRF binding (P = 0.0172)
MVP		0.40
MPC		1.4
ClinPred		0.021	T
GERP RS		-2.4
PromoterAI		0.024	Neutral
Varity_R		0.080
gMVP		0.12
Mutation Taster		=100/0	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: rs2645329; hg19: chr5-178421770;