chr5-178988936-A-G

Variant names:

• chr5-178988936-A-G
• rs2067011
• NM_000843.4:c.1353T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_000843.4(GRM6):​c.1353T>C​(p.Asn451Asn) 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
• Publications: 28 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.227).
• BP6: Variant 5-178988936-A-G is Benign according to our data. Variant chr5-178988936-A-G is described in ClinVar as Benign. ClinVar VariationId is 99627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1353T>C	p.Asn451Asn	splice_region synonymous	Exon 7 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.1353T>C	p.Asn451Asn	splice_region synonymous	Exon 7 of 11	ENSP00000430767.1
	GRM6	ENST00000231188.9	TSL:2	c.1353T>C	p.Asn451Asn	splice_region synonymous	Exon 6 of 10	ENSP00000231188.5
	GRM6	ENST00000650031.1		c.1353T>C	p.Asn451Asn	splice_region synonymous	Exon 8 of 12	ENSP00000497110.1

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

GnomAD2 exomes AF: 0.532 AC: 130866 AN: 246060 AF XY: 0.526

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 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

African (AFR) AF: 0.405 AC: 13541 AN: 33400

American (AMR) AF: 0.569 AC: 25351 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 12564 AN: 26082

East Asian (EAS) AF: 0.553 AC: 21935 AN: 39650

South Asian (SAS) AF: 0.462 AC: 39680 AN: 85970

European-Finnish (FIN) AF: 0.569 AC: 30320 AN: 53240

Middle Eastern (MID) AF: 0.421 AC: 2080 AN: 4944

European-Non Finnish (NFE) AF: 0.559 AC: 620043 AN: 1109546

Other (OTH) AF: 0.535 AC: 32209 AN: 60192

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

African (AFR) AF: 0.412 AC: 17071 AN: 41470

American (AMR) AF: 0.531 AC: 8111 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 1679 AN: 3470

East Asian (EAS) AF: 0.570 AC: 2925 AN: 5128

South Asian (SAS) AF: 0.481 AC: 2320 AN: 4820

European-Finnish (FIN) AF: 0.567 AC: 5995 AN: 10566

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37533 AN: 67928

Other (OTH) AF: 0.483 AC: 1018 AN: 2106

Alfa AF: 0.536 Hom.: 96817

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

Nov 23, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2 Other:1

Mar 03, 2015

GeneDx

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.47
CADD	Benign	2.2
DANN	Benign	0.80
PhyloP100		-1.1
Mutation Taster		=71/29	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2067011; hg19: chr5-178415937; COSMIC: COSV51447399; COSMIC: COSV51447399;