rs2067011

chr5-178988936-A-Gchr5-178988936-A-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.1353T>C(p.Asn451=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,609,530 control chromosomes in the GnomAD database, including 239,795 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (19954 hom., cov: 32)
  • Exomes 𝑓: 0.55 (219841 hom.)
• Consequence: GRM6 NM_000843.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001885
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.06

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=-0.47).
• BP6: Variant 5-178988936-A-G is Benign according to our data. Variant chr5-178988936-A-G is described in ClinVar as [Benign]. Clinvar id is 99627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-178988936-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM6	NM_000843.4	c.1353T>C	p.Asn451=	splice_region_variant, synonymous_variant	7/11	ENST00000517717.3
ZNF454	XR_007058600.1	n.5644-811A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM6	ENST00000517717.3	c.1353T>C	p.Asn451=	splice_region_variant, synonymous_variant	7/11	5	NM_000843.4	P1
	ENST00000519491.1	n.305-811A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.507 AC: 76999 AN: 151864 Hom.: 19925 Cov.: 32

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.478

GnomAD3 exomes AF: 0.532 AC: 130866 AN: 246060 Hom.: 35216 AF XY: 0.526 AC XY: 70212 AN XY: 133386

Gnomad AFR exome AF: 0.406

Gnomad AMR exome AF: 0.572

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.584

Gnomad SAS exome AF: 0.462

Gnomad FIN exome AF: 0.566

Gnomad NFE exome AF: 0.546

Gnomad OTH exome AF: 0.528

GnomAD4 exome AF: 0.547 AC: 797723 AN: 1457548 Hom.: 219841 Cov.: 35 AF XY: 0.543 AC XY: 393665 AN XY: 725056

Gnomad4 AFR exome AF: 0.405

Gnomad4 AMR exome AF: 0.569

Gnomad4 ASJ exome AF: 0.482

Gnomad4 EAS exome AF: 0.553

Gnomad4 SAS exome AF: 0.462

Gnomad4 FIN exome AF: 0.569

Gnomad4 NFE exome AF: 0.559

Gnomad4 OTH exome AF: 0.535

GnomAD4 genome AF: 0.507 AC: 77071 AN: 151982 Hom.: 19954 Cov.: 32 AF XY: 0.509 AC XY: 37825 AN XY: 74278

Gnomad4 AFR AF: 0.412

Gnomad4 AMR AF: 0.531

Gnomad4 ASJ AF: 0.484

Gnomad4 EAS AF: 0.570

Gnomad4 SAS AF: 0.481

Gnomad4 FIN AF: 0.567

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.483

Alfa AF: 0.536 Hom.: 41718

Bravo AF: 0.501

Asia WGS AF: 0.561 AC: 1950 AN: 3478

EpiCase AF: 0.529

EpiControl AF: 0.519

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Invitae	Jan 31, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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	-0.47
Cadd	Benign	2.2
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.020		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: rs2067011; hg19: chr5-178415937; COSMIC: COSV51447399; COSMIC: COSV51447399;