5-178989287-G-A

Position:

• chr5-178989287-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000843.4(GRM6):​c.1131C>T​(p.Asp377Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 1,610,862 control chromosomes in the GnomAD database, including 448,766 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41165 hom., cov: 24)
  • Exomes 𝑓: 0.75 (407601 hom.)
• Consequence: GRM6 NM_000843.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• 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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-178989287-G-A is Benign according to our data. Variant chr5-178989287-G-A is described in ClinVar as [Benign]. Clinvar id is 99625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-178989287-G-A is described in Lovd as [Likely_benign]. Variant chr5-178989287-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM6	NM_000843.4	c.1131C>T	p.Asp377Asp	synonymous_variant	6/11	ENST00000517717.3	NP_000834.2
ZNF454	XR_007058600.1	n.5644-460G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM6	ENST00000517717.3	c.1131C>T	p.Asp377Asp	synonymous_variant	6/11	5	NM_000843.4	ENSP00000430767.1
GRM6	ENST00000231188.9	c.1131C>T	p.Asp377Asp	synonymous_variant	5/10	2		ENSP00000231188.5
GRM6	ENST00000650031.1	c.1131C>T	p.Asp377Asp	synonymous_variant	7/12			ENSP00000497110.1
ENSG00000254035	ENST00000519491.1	n.305-460G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.740 AC: 110789 AN: 149682 Hom.: 41126 Cov.: 24

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.646

Gnomad EAS AF: 0.707

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.672

Gnomad NFE AF: 0.755

Gnomad OTH AF: 0.713

GnomAD3 exomes AF: 0.723 AC: 181643 AN: 251364 Hom.: 66028 AF XY: 0.719 AC XY: 97660 AN XY: 135852

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.668

Gnomad ASJ exome AF: 0.641

Gnomad EAS exome AF: 0.703

Gnomad SAS exome AF: 0.652

Gnomad FIN exome AF: 0.795

Gnomad NFE exome AF: 0.750

Gnomad OTH exome AF: 0.726

GnomAD4 exome AF: 0.746 AC: 1089419 AN: 1461070 Hom.: 407601 Cov.: 46 AF XY: 0.742 AC XY: 539050 AN XY: 726852

Gnomad4 AFR exome AF: 0.752

Gnomad4 AMR exome AF: 0.674

Gnomad4 ASJ exome AF: 0.644

Gnomad4 EAS exome AF: 0.663

Gnomad4 SAS exome AF: 0.655

Gnomad4 FIN exome AF: 0.793

Gnomad4 NFE exome AF: 0.759

Gnomad4 OTH exome AF: 0.740

GnomAD4 genome AF: 0.740 AC: 110880 AN: 149792 Hom.: 41165 Cov.: 24 AF XY: 0.739 AC XY: 53917 AN XY: 72942

Gnomad4 AFR AF: 0.754

Gnomad4 AMR AF: 0.676

Gnomad4 ASJ AF: 0.646

Gnomad4 EAS AF: 0.706

Gnomad4 SAS AF: 0.660

Gnomad4 FIN AF: 0.800

Gnomad4 NFE AF: 0.755

Gnomad4 OTH AF: 0.715

Alfa AF: 0.742 Hom.: 49475

Bravo AF: 0.731

Asia WGS AF: 0.716 AC: 2487 AN: 3476

EpiCase AF: 0.733

EpiControl AF: 0.731

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 07, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Congenital stationary night blindness 1B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.35
DANN	Benign	0.43

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: rs2071246; hg19: chr5-178416288; COSMIC: COSV51438312; COSMIC: COSV51438312;