NM_000843.4:c.19G>A

Variant names:

• chr5-178994926-C-T
• rs62642053
• NM_000843.4:c.19G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000843.4(GRM6):​c.19G>A​(p.Ala7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00762 in 1,189,594 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0078 (45 hom.)
• Consequence: GRM6 NM_000843.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.52
• Publications: 3 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: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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=0.0041314065).
• BP6: Variant 5-178994926-C-T is Benign according to our data. Variant chr5-178994926-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00617 (935/151488) while in subpopulation NFE AF = 0.00915 (619/67644). AF 95% confidence interval is 0.00855. There are 6 homozygotes in GnomAd4. There are 439 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

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.19G>A	p.Ala7Thr	missense	Exon 2 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.19G>A	p.Ala7Thr	missense	Exon 2 of 11	ENSP00000430767.1
	GRM6	ENST00000231188.9	TSL:2	c.19G>A	p.Ala7Thr	missense	Exon 1 of 10	ENSP00000231188.5
	GRM6	ENST00000650031.1		c.19G>A	p.Ala7Thr	missense	Exon 3 of 12	ENSP00000497110.1

Frequencies

GnomAD3 genomes AF: 0.00619 AC: 937 AN: 151380 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00710

Gnomad ASJ AF: 0.0200

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00470

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00915

Gnomad OTH AF: 0.00816

GnomAD2 exomes AF: 0.0102 AC: 39 AN: 3836 AF XY: 0.0109

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00862

GnomAD4 exome AF: 0.00783 AC: 8125 AN: 1038106 Hom.: 45 Cov.: 32 AF XY: 0.00777 AC XY: 3835 AN XY: 493400

African (AFR) AF: 0.000672 AC: 14 AN: 20838

American (AMR) AF: 0.00749 AC: 54 AN: 7214

Ashkenazi Jewish (ASJ) AF: 0.0174 AC: 207 AN: 11928

East Asian (EAS) AF: 0.0000466 AC: 1 AN: 21482

South Asian (SAS) AF: 0.00366 AC: 82 AN: 22378

European-Finnish (FIN) AF: 0.00400 AC: 74 AN: 18496

Middle Eastern (MID) AF: 0.0136 AC: 36 AN: 2642

European-Non Finnish (NFE) AF: 0.00825 AC: 7368 AN: 893322

Other (OTH) AF: 0.00726 AC: 289 AN: 39806

GnomAD4 genome AF: 0.00617 AC: 935 AN: 151488 Hom.: 6 Cov.: 33 AF XY: 0.00593 AC XY: 439 AN XY: 73992

African (AFR) AF: 0.00145 AC: 60 AN: 41456

American (AMR) AF: 0.00709 AC: 108 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0200 AC: 69 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.00470 AC: 49 AN: 10424

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00915 AC: 619 AN: 67644

Other (OTH) AF: 0.00807 AC: 17 AN: 2106

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00605

ExAC AF: 0.00156 AC: 25

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.27
DANN	Benign	0.97
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.11	N
REVEL	Benign	0.16
Sift	Benign	0.60	T
Sift4G	Benign	0.66	T
Polyphen		0.0010	B
Vest4		0.070
MVP		0.33
MPC		1.2
ClinPred		0.0073	T
GERP RS		-1.6
PromoterAI		-0.014	Neutral
Varity_R		0.023
gMVP		0.38
Mutation Taster		=98/2	polymorphism

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: rs62642053; hg19: chr5-178421927; COSMIC: COSV51432913; COSMIC: COSV51432913;