5-178994812-ACAGGCCGCCCAGCGT-ACAGGCCGCCCAGCGTCAGGCCGCCCAGCGT

Position:

• chr5-178994812-ACAGGCCGCCCAGCGT-ACAGGCCGCCCAGCGTCAGGCCGCCCAGCGT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000843.4(GRM6):​c.132_133insACGCTGGGCGGCCTG​(p.Thr40_Leu44dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000157 in 1,274,678 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: GRM6 NM_000843.4 inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000843.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM6	NM_000843.4	c.132_133insACGCTGGGCGGCCTG	p.Thr40_Leu44dup	inframe_insertion	2/11	ENST00000517717.3	NP_000834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM6	ENST00000517717.3	c.132_133insACGCTGGGCGGCCTG	p.Thr40_Leu44dup	inframe_insertion	2/11	5	NM_000843.4	ENSP00000430767	P1
GRM6	ENST00000231188.9	c.132_133insACGCTGGGCGGCCTG	p.Thr40_Leu44dup	inframe_insertion	1/10	2		ENSP00000231188	P1
GRM6	ENST00000650031.1	c.132_133insACGCTGGGCGGCCTG	p.Thr40_Leu44dup	inframe_insertion	3/12			ENSP00000497110	P1

Frequencies

GnomAD3 genomes AF: 0.00000670 AC: 1 AN: 149298 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

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 AF: 8.89e-7 AC: 1 AN: 1125380 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 546668

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000106

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000670 AC: 1 AN: 149298 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 72808

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1237461749; hg19: chr5-178421813;