5-178994769-T-G

Variant names:

• chr5-178994769-T-G
• rs2645329
• NM_000843.4:c.176A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000843.4(GRM6):​c.176A>C​(p.Gln59Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,369,858 control chromosomes in the GnomAD database, including 240,162 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q59Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.57 (24597 hom., cov: 34)
  • Exomes 𝑓: 0.59 (215565 hom.)
• Consequence: GRM6 NM_000843.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.195
• Publications: 22 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]

GRM6 Gene-Disease associations (from GenCC):

• congenital stationary night blindness 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• GRM6-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1140935E-5).
• BP6: Variant 5-178994769-T-G is Benign according to our data. Variant chr5-178994769-T-G is described in ClinVar as Benign. ClinVar VariationId is 93438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.594 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM6	NM_000843.4	MANE Select	c.176A>C	p.Gln59Pro	missense	Exon 2 of 11	NP_000834.2	O15303

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM6	ENST00000517717.3	TSL:5 MANE Select	c.176A>C	p.Gln59Pro	missense	Exon 2 of 11	ENSP00000430767.1	O15303
	GRM6	ENST00000231188.9	TSL:2	c.176A>C	p.Gln59Pro	missense	Exon 1 of 10	ENSP00000231188.5	O15303
	GRM6	ENST00000650031.1		c.176A>C	p.Gln59Pro	missense	Exon 3 of 12	ENSP00000497110.1	O15303

Frequencies

GnomAD3 genomes AF: 0.571 AC: 85484 AN: 149760 Hom.: 24568 Cov.: 34

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.533

GnomAD2 exomes AF: 0.550 AC: 37270 AN: 67784 AF XY: 0.539

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.584

Gnomad ASJ exome AF: 0.503

Gnomad EAS exome AF: 0.546

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.584

Gnomad OTH exome AF: 0.552

GnomAD4 exome AF: 0.591 AC: 720965 AN: 1219992 Hom.: 215565 Cov.: 41 AF XY: 0.586 AC XY: 351108 AN XY: 599334

African (AFR) AF: 0.528 AC: 13273 AN: 25142

American (AMR) AF: 0.573 AC: 12583 AN: 21942

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 9980 AN: 20160

East Asian (EAS) AF: 0.545 AC: 13900 AN: 25496

South Asian (SAS) AF: 0.450 AC: 26539 AN: 58974

European-Finnish (FIN) AF: 0.626 AC: 17999 AN: 28762

Middle Eastern (MID) AF: 0.438 AC: 1517 AN: 3464

European-Non Finnish (NFE) AF: 0.605 AC: 597334 AN: 987550

Other (OTH) AF: 0.574 AC: 27840 AN: 48502

GnomAD4 genome AF: 0.571 AC: 85561 AN: 149866 Hom.: 24597 Cov.: 34 AF XY: 0.572 AC XY: 41803 AN XY: 73122

African (AFR) AF: 0.533 AC: 21998 AN: 41260

American (AMR) AF: 0.563 AC: 8479 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1755 AN: 3438

East Asian (EAS) AF: 0.574 AC: 2925 AN: 5092

South Asian (SAS) AF: 0.501 AC: 2418 AN: 4828

European-Finnish (FIN) AF: 0.638 AC: 6217 AN: 9750

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.599 AC: 40191 AN: 67152

Other (OTH) AF: 0.537 AC: 1123 AN: 2090

Alfa AF: 0.579 Hom.: 17041

Bravo AF: 0.567

ESP6500AA AF: 0.606 AC: 1561

ESP6500EA AF: 0.652 AC: 3170

ExAC AF: 0.439 AC: 17229

Asia WGS AF: 0.554 AC: 1767 AN: 3188

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (3)
-	-	1	Congenital stationary night blindness 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.4
DANN	Benign	0.72
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.000021	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.20
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.14
Sift	Benign	0.92	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.060
MPC		1.5
ClinPred		0.0032	T
GERP RS		-2.4
PromoterAI		0.018	Neutral
Varity_R		0.11
gMVP		0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2645329; hg19: chr5-178421770; COSMIC: COSV51442230; COSMIC: COSV51442230;