rs62642053

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-178994926-C-A
• chr5-178994926-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000843.4(GRM6):​c.19G>T​(p.Ala7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRM6 NM_000843.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05425769).

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>T	p.Ala7Ser	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>T	p.Ala7Ser	missense	Exon 2 of 11	ENSP00000430767.1
	GRM6	ENST00000231188.9	TSL:2	c.19G>T	p.Ala7Ser	missense	Exon 1 of 10	ENSP00000231188.5
	GRM6	ENST00000650031.1		c.19G>T	p.Ala7Ser	missense	Exon 3 of 12	ENSP00000497110.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151380 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1038118 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 493406

African (AFR) AF: 0.00 AC: 0 AN: 20838

American (AMR) AF: 0.00 AC: 0 AN: 7214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11930

East Asian (EAS) AF: 0.00 AC: 0 AN: 21482

South Asian (SAS) AF: 0.00 AC: 0 AN: 22378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 893330

Other (OTH) AF: 0.00 AC: 0 AN: 39806

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151380 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73874

African (AFR) AF: 0.0000484 AC: 2 AN: 41338

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67654

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.083
DANN	Benign	0.92
DEOGEN2	Benign	0.091	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.092
Sift	Benign	0.78	T
Sift4G	Benign	0.81	T
Polyphen		0.015	B
Vest4		0.070
MutPred		0.36		Gain of phosphorylation at A7 (P = 0.0055)
MVP		0.50
MPC		1.1
ClinPred		0.047	T
GERP RS		-1.6
PromoterAI		0.012	Neutral
Varity_R		0.033
gMVP		0.30
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;