rs2645339

chr5-178989062-G-Achr5-178989062-G-Cchr5-178989062-G-T

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.1227C>T(p.Tyr409=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,613,020 control chromosomes in the GnomAD database, including 237,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19491 hom., cov: 33)
  • Exomes 𝑓: 0.54 (217556 hom.)
• Consequence: GRM6 NM_000843.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.947

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 5-178989062-G-A is Benign according to our data. Variant chr5-178989062-G-A is described in ClinVar as [Benign]. Clinvar id is 99626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-178989062-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.947 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM6	NM_000843.4	c.1227C>T	p.Tyr409=	synonymous_variant	7/11	ENST00000517717.3
ZNF454	XR_007058600.1	n.5644-685G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM6	ENST00000517717.3	c.1227C>T	p.Tyr409=	synonymous_variant	7/11	5	NM_000843.4	P1
	ENST00000519491.1	n.305-685G>A		intron_variant, non_coding_transcript_variant		3
GRM6	ENST00000231188.9	c.1227C>T	p.Tyr409=	synonymous_variant	6/10	2		P1
GRM6	ENST00000650031.1	c.1227C>T	p.Tyr409=	synonymous_variant	8/12			P1

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75981 AN: 151878 Hom.: 19464 Cov.: 33

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.565

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.472

GnomAD3 exomes AF: 0.528 AC: 131968 AN: 249712 Hom.: 35359 AF XY: 0.523 AC XY: 70667 AN XY: 135144

Gnomad AFR exome AF: 0.398

Gnomad AMR exome AF: 0.571

Gnomad ASJ exome AF: 0.475

Gnomad EAS exome AF: 0.581

Gnomad SAS exome AF: 0.453

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.545

Gnomad OTH exome AF: 0.526

GnomAD4 exome AF: 0.544 AC: 794400 AN: 1461024 Hom.: 217556 Cov.: 49 AF XY: 0.539 AC XY: 391933 AN XY: 726812

Gnomad4 AFR exome AF: 0.392

Gnomad4 AMR exome AF: 0.568

Gnomad4 ASJ exome AF: 0.474

Gnomad4 EAS exome AF: 0.551

Gnomad4 SAS exome AF: 0.452

Gnomad4 FIN exome AF: 0.562

Gnomad4 NFE exome AF: 0.556

Gnomad4 OTH exome AF: 0.531

GnomAD4 genome AF: 0.500 AC: 76047 AN: 151996 Hom.: 19491 Cov.: 33 AF XY: 0.502 AC XY: 37288 AN XY: 74310

Gnomad4 AFR AF: 0.399

Gnomad4 AMR AF: 0.528

Gnomad4 ASJ AF: 0.477

Gnomad4 EAS AF: 0.564

Gnomad4 SAS AF: 0.471

Gnomad4 FIN AF: 0.560

Gnomad4 NFE AF: 0.548

Gnomad4 OTH AF: 0.478

Alfa AF: 0.524 Hom.: 10638

Bravo AF: 0.496

Asia WGS AF: 0.551 AC: 1915 AN: 3478

EpiCase AF: 0.525

EpiControl AF: 0.518

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	-0.56
Cadd	Benign	3.5
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs2645339; hg19: chr5-178416063; COSMIC: COSV51442180; COSMIC: COSV51442180;