chr5-178988936-A-T

Variant names:

• chr5-178988936-A-T
• rs2067011
• NM_000843.4:c.1353T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000843.4(GRM6):​c.1353T>A​(p.Asn451Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. N451S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRM6 NM_000843.4 missense, splice_region
• Scores: Splicing: ADA: 0.00009508
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 28 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]

ENSG00000254035 (HGNC:):

ZNF454 (HGNC:21200): (zinc finger protein 454) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity GRM6_HUMAN
• PM2: Very rare variant in population databases, with high coverage

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.1353T>A	p.Asn451Lys	missense splice_region	Exon 7 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.1353T>A	p.Asn451Lys	missense splice_region	Exon 7 of 11	ENSP00000430767.1
	GRM6	ENST00000231188.9	TSL:2	c.1353T>A	p.Asn451Lys	missense splice_region	Exon 6 of 10	ENSP00000231188.5
	GRM6	ENST00000650031.1		c.1353T>A	p.Asn451Lys	missense splice_region	Exon 8 of 12	ENSP00000497110.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1458890 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 725670

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4954

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110714

Other (OTH) AF: 0.00 AC: 0 AN: 60236

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 96817

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.5	L
PhyloP100		-1.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.44
Sift	Benign	0.36	T
Sift4G	Benign	0.84	T
Polyphen		0.044	B
Vest4		0.66
MutPred		0.62		Gain of ubiquitination at N451 (P = 0.0369)
MVP		0.90
MPC		0.13
ClinPred		0.17	T
GERP RS		-4.4
Varity_R		0.30
gMVP		0.32
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000095
dbscSNV1_RF	Benign	0.31
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: rs2067011; hg19: chr5-178415937;