5-178986946-T-C

Variant names:

• chr5-178986946-T-C
• rs11746675
• NM_000843.4:c.1392A>G

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.1392A>G​(p.Gly464Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,613,232 control chromosomes in the GnomAD database, including 319,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25577 hom., cov: 33)
  • Exomes 𝑓: 0.63 (294376 hom.)
• Consequence: GRM6 NM_000843.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.891
• Publications: 20 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=-0.66).
• BP6: Variant 5-178986946-T-C is Benign according to our data. Variant chr5-178986946-T-C is described in ClinVar as Benign. ClinVar VariationId is 99628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.891 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.642 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.1392A>G	p.Gly464Gly	synonymous	Exon 8 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.1392A>G	p.Gly464Gly	synonymous	Exon 8 of 11	ENSP00000430767.1
	GRM6	ENST00000231188.9	TSL:2	c.1392A>G	p.Gly464Gly	synonymous	Exon 7 of 10	ENSP00000231188.5
	GRM6	ENST00000650031.1		c.1392A>G	p.Gly464Gly	synonymous	Exon 9 of 12	ENSP00000497110.1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86838 AN: 151892 Hom.: 25551 Cov.: 33

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.553

GnomAD2 exomes AF: 0.600 AC: 149877 AN: 249822 AF XY: 0.596

Gnomad AFR exome AF: 0.431

Gnomad AMR exome AF: 0.620

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.582

Gnomad FIN exome AF: 0.621

Gnomad NFE exome AF: 0.645

Gnomad OTH exome AF: 0.606

GnomAD4 exome AF: 0.632 AC: 923228 AN: 1461220 Hom.: 294376 Cov.: 51 AF XY: 0.627 AC XY: 455474 AN XY: 726890

African (AFR) AF: 0.427 AC: 14293 AN: 33474

American (AMR) AF: 0.619 AC: 27625 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 15850 AN: 26134

East Asian (EAS) AF: 0.557 AC: 22099 AN: 39674

South Asian (SAS) AF: 0.492 AC: 42448 AN: 86222

European-Finnish (FIN) AF: 0.625 AC: 33313 AN: 53334

Middle Eastern (MID) AF: 0.489 AC: 2821 AN: 5768

European-Non Finnish (NFE) AF: 0.655 AC: 727853 AN: 1111628

Other (OTH) AF: 0.612 AC: 36926 AN: 60368

GnomAD4 genome AF: 0.572 AC: 86910 AN: 152012 Hom.: 25577 Cov.: 33 AF XY: 0.569 AC XY: 42266 AN XY: 74304

African (AFR) AF: 0.436 AC: 18055 AN: 41458

American (AMR) AF: 0.601 AC: 9187 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2114 AN: 3472

East Asian (EAS) AF: 0.568 AC: 2906 AN: 5118

South Asian (SAS) AF: 0.506 AC: 2437 AN: 4820

European-Finnish (FIN) AF: 0.615 AC: 6520 AN: 10602

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 43940 AN: 67940

Other (OTH) AF: 0.558 AC: 1179 AN: 2112

Alfa AF: 0.611 Hom.: 73652

Bravo AF: 0.568

Asia WGS AF: 0.572 AC: 1989 AN: 3478

EpiCase AF: 0.624

EpiControl AF: 0.619

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

not specified Benign:1

Mar 19, 2015

Eurofins Ntd Llc (ga)

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	-0.66
CADD	Benign	10
DANN	Benign	0.48
PhyloP100		-0.89
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11746675; hg19: chr5-178413947; COSMIC: COSV51442155; COSMIC: COSV51442155;