5-178989287-G-C

Position:

• chr5-178989287-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000843.4(GRM6):​c.1131C>G​(p.Asp377Glu) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D377D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: GRM6 NM_000843.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.78

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]

ENSG00000254035 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059488207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM6	NM_000843.4	c.1131C>G	p.Asp377Glu	missense_variant	6/11	ENST00000517717.3	NP_000834.2
ZNF454	XR_007058600.1	n.5644-460G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM6	ENST00000517717.3	c.1131C>G	p.Asp377Glu	missense_variant	6/11	5	NM_000843.4	ENSP00000430767.1
GRM6	ENST00000231188.9	c.1131C>G	p.Asp377Glu	missense_variant	5/10	2		ENSP00000231188.5
GRM6	ENST00000650031.1	c.1131C>G	p.Asp377Glu	missense_variant	7/12			ENSP00000497110.1
ENSG00000254035	ENST00000519491.1	n.305-460G>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.0030
DANN	Benign	0.37
DEOGEN2	Benign	0.094	T;T;T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.50	T;.;.
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.65	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.23	N;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.57	T;T;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	B;B;B
Vest4		0.048
MutPred		0.39		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.42
MPC		0.096
ClinPred		0.032	T
GERP RS		-10
Varity_R		0.027
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs2071246; hg19: chr5-178416288;