5-178994808-G-T

Variant names:

• chr5-178994808-G-T
• rs62638197
• NM_000843.4:c.137C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000843.4(GRM6):​c.137C>A​(p.Pro46Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000884 in 1,130,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P46L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: GRM6 NM_000843.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.35
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-178994808-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 5844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

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.137C>A	p.Pro46Gln	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.137C>A	p.Pro46Gln	missense	Exon 2 of 11	ENSP00000430767.1	O15303
	GRM6	ENST00000231188.9	TSL:2	c.137C>A	p.Pro46Gln	missense	Exon 1 of 10	ENSP00000231188.5	O15303
	GRM6	ENST00000650031.1		c.137C>A	p.Pro46Gln	missense	Exon 3 of 12	ENSP00000497110.1	O15303

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.84e-7 AC: 1 AN: 1130906 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 549874

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22806

American (AMR) AF: 0.00 AC: 0 AN: 11980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15310

East Asian (EAS) AF: 0.00 AC: 0 AN: 23848

South Asian (SAS) AF: 0.0000251 AC: 1 AN: 39878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3014

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 945622

Other (OTH) AF: 0.00 AC: 0 AN: 44322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.44	B
Vest4		0.57
MutPred		0.74		Gain of MoRF binding (P = 0.0221)
MVP		0.80
MPC		1.8
ClinPred		0.99	D
GERP RS		3.2
PromoterAI		-0.12	Neutral
Varity_R		0.36
gMVP		0.63
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs62638197; hg19: chr5-178421809;