NM_000843.4:c.118_132dupACGCTGGGCGGCCTG

Variant names:

• chr5-178994812-A-ACAGGCCGCCCAGCGT
• rs1237461749
• NM_000843.4:c.118_132dupACGCTGGGCGGCCTG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_000843.4(GRM6):​c.118_132dupACGCTGGGCGGCCTG​(p.Leu44_Phe45insThrLeuGlyGlyLeu) variant causes a conservative 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000843.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM6	NM_000843.4	c.118_132dupACGCTGGGCGGCCTG	p.Leu44_Phe45insThrLeuGlyGlyLeu	conservative_inframe_insertion	Exon 2 of 11	ENST00000517717.3	NP_000834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM6	ENST00000517717.3	c.118_132dupACGCTGGGCGGCCTG	p.Leu44_Phe45insThrLeuGlyGlyLeu	conservative_inframe_insertion	Exon 2 of 11	5	NM_000843.4	ENSP00000430767.1
GRM6	ENST00000231188.9	c.118_132dupACGCTGGGCGGCCTG	p.Leu44_Phe45insThrLeuGlyGlyLeu	conservative_inframe_insertion	Exon 1 of 10	2		ENSP00000231188.5
GRM6	ENST00000650031.1	c.118_132dupACGCTGGGCGGCCTG	p.Leu44_Phe45insThrLeuGlyGlyLeu	conservative_inframe_insertion	Exon 3 of 12			ENSP00000497110.1

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

⚠️ 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: 22660

American (AMR) AF: 0.00 AC: 0 AN: 11714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14962

East Asian (EAS) AF: 0.00 AC: 0 AN: 23636

South Asian (SAS) AF: 0.00 AC: 0 AN: 38914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2990

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 942676

Other (OTH) AF: 0.00 AC: 0 AN: 44028

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

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

African (AFR) AF: 0.00 AC: 0 AN: 41118

American (AMR) AF: 0.00 AC: 0 AN: 14984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67012

Other (OTH) AF: 0.00 AC: 0 AN: 2052

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0040
Mutation Taster		=66/34	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1237461749; hg19: chr5-178421813;