5-178981486-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000843.4(GRM6):c.*171A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0465 in 601,440 control chromosomes in the GnomAD database, including 1,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (176 hom., cov: 32)
  • Exomes 𝑓: 0.050 (923 hom.)
• Consequence: GRM6 NM_000843.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.444

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-178981486-T-C is Benign according to our data. Variant chr5-178981486-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1706654.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM6	NM_000843.4	c.*171A>G		3_prime_UTR_variant	11/11	ENST00000517717.3
ZNF454	XR_007058600.1	n.5644-8261T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM6	ENST00000517717.3	c.*171A>G		3_prime_UTR_variant	11/11	5	NM_000843.4	P1
	ENST00000519491.1	n.305-8261T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5421 AN: 152006 Hom.: 175 Cov.: 32

Gnomad AFR AF: 0.00674

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0576

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0854

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0341

Gnomad OTH AF: 0.0449

GnomAD4 exome AF: 0.0502 AC: 22543 AN: 449316 Hom.: 923 Cov.: 4 AF XY: 0.0538 AC XY: 12732 AN XY: 236670

Gnomad4 AFR exome AF: 0.00805

Gnomad4 AMR exome AF: 0.0471

Gnomad4 ASJ exome AF: 0.0580

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.0917

Gnomad4 FIN exome AF: 0.0356

Gnomad4 NFE exome AF: 0.0345

Gnomad4 OTH exome AF: 0.0458

GnomAD4 genome AF: 0.0356 AC: 5421 AN: 152124 Hom.: 176 Cov.: 32 AF XY: 0.0378 AC XY: 2814 AN XY: 74352

Gnomad4 AFR AF: 0.00670

Gnomad4 AMR AF: 0.0575

Gnomad4 ASJ AF: 0.0620

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.0852

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0341

Gnomad4 OTH AF: 0.0454

Alfa AF: 0.0354 Hom.: 29

Bravo AF: 0.0333

Asia WGS AF: 0.0930 AC: 323 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 28, 2020

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.6
Dann	Benign	0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs17078848; hg19: chr5-178408487;