5-178989287-G-A

Variant names:

• chr5-178989287-G-A
• rs2071246
• NM_000843.4:c.1131C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 23 publications found

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:):

ZNF454 (HGNC:21200): (zinc finger protein 454) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 99625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000843.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM6	NM_000843.4	MANE Select	c.1131C>T	p.Asp377Asp	synonymous	Exon 6 of 11	NP_000834.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM6	ENST00000517717.3	TSL:5 MANE Select	c.1131C>T	p.Asp377Asp	synonymous	Exon 6 of 11	ENSP00000430767.1
	GRM6	ENST00000231188.9	TSL:2	c.1131C>T	p.Asp377Asp	synonymous	Exon 5 of 10	ENSP00000231188.5
	GRM6	ENST00000650031.1		c.1131C>T	p.Asp377Asp	synonymous	Exon 7 of 12	ENSP00000497110.1

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

GnomAD2 exomes AF: 0.723 AC: 181643 AN: 251364 AF XY: 0.719

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 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

African (AFR) AF: 0.752 AC: 25158 AN: 33464

American (AMR) AF: 0.674 AC: 30125 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 16820 AN: 26128

East Asian (EAS) AF: 0.663 AC: 26304 AN: 39690

South Asian (SAS) AF: 0.655 AC: 56478 AN: 86230

European-Finnish (FIN) AF: 0.793 AC: 42363 AN: 53392

Middle Eastern (MID) AF: 0.665 AC: 3781 AN: 5686

European-Non Finnish (NFE) AF: 0.759 AC: 843708 AN: 1111414

Other (OTH) AF: 0.740 AC: 44682 AN: 60352

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

African (AFR) AF: 0.754 AC: 30627 AN: 40594

American (AMR) AF: 0.676 AC: 10151 AN: 15016

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 2229 AN: 3452

East Asian (EAS) AF: 0.706 AC: 3510 AN: 4970

South Asian (SAS) AF: 0.660 AC: 3117 AN: 4720

European-Finnish (FIN) AF: 0.800 AC: 8151 AN: 10192

Middle Eastern (MID) AF: 0.656 AC: 189 AN: 288

European-Non Finnish (NFE) AF: 0.755 AC: 51033 AN: 67588

Other (OTH) AF: 0.715 AC: 1481 AN: 2070

Alfa AF: 0.743 Hom.: 63689

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 07, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2 Other:1

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital stationary night blindness 1B Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.35
DANN	Benign	0.43
PhyloP100		-1.8
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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