rs201396068

Positions:

• chr5-178986717-C-A
• chr5-178986717-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000843.4(GRM6):​c.1537G>T​(p.Val513Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. V513M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRM6 NM_000843.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-178986717-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.11963615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM6	NM_000843.4	c.1537G>T	p.Val513Leu	missense_variant	9/11	ENST00000517717.3	NP_000834.2
ZNF454	XR_007058600.1	n.5644-3030C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM6	ENST00000517717.3	c.1537G>T	p.Val513Leu	missense_variant	9/11	5	NM_000843.4	ENSP00000430767.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.099	T;T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.48	T;.;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.49	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.020	N;N;.
REVEL	Benign	0.23
Sift	Benign	0.74	T;T;.
Sift4G	Benign	0.77	T;T;.
Polyphen		0.0	B;B;B
Vest4		0.15
MutPred		0.45		Gain of catalytic residue at V513 (P = 0.0104);Gain of catalytic residue at V513 (P = 0.0104);Gain of catalytic residue at V513 (P = 0.0104);
MVP		0.82
MPC		0.099
ClinPred		0.10	T
GERP RS		3.8
Varity_R		0.079
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201396068; hg19: chr5-178413718;