4-92304774-A-C

Variant names:

• chr4-92304774-A-C
• rs114432116
• NM_001510.4:c.88+30A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001510.4(GRID2):​c.88+30A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000758 in 1,318,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: GRID2 NM_001510.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00
• Publications: 0 publications found

Genes affected

GRID2 (HGNC:4576): (glutamate ionotropic receptor delta type subunit 2) The protein encoded by this gene is a member of the family of ionotropic glutamate receptors which are the predominant excitatory neurotransmitter receptors in the mammalian brain. The encoded protein is a multi-pass membrane protein that is expressed selectively in cerebellar Purkinje cells. A point mutation in the mouse ortholog, associated with the phenotype named 'lurcher', in the heterozygous state leads to ataxia resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development. Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis. This protein also plays a role in synapse organization between parallel fibers and Purkinje cells. Alternate splicing results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause cerebellar ataxia in humans. [provided by RefSeq, Apr 2014]

GRID2 Gene-Disease associations (from GenCC):

• autosomal recessive spinocerebellar ataxia 18

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001510.4. 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
	GRID2	NM_001510.4	MANE Select	c.88+30A>C		intron	N/A	NP_001501.2	O43424-1
	GRID2	NM_001440459.1		c.88+30A>C		intron	N/A	NP_001427388.1
	GRID2	NM_001286838.1		c.88+30A>C		intron	N/A	NP_001273767.1	O43424-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRID2	ENST00000282020.9	TSL:1 MANE Select	c.88+30A>C		intron	N/A	ENSP00000282020.4	O43424-1
	GRID2	ENST00000510992.5	TSL:1	c.88+30A>C		intron	N/A	ENSP00000421257.1	O43424-2
	GRID2	ENST00000505687.5	TSL:1	n.260+30A>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.58e-7 AC: 1 AN: 1318878 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 664162

African (AFR) AF: 0.00 AC: 0 AN: 30848

American (AMR) AF: 0.00 AC: 0 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25298

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39060

South Asian (SAS) AF: 0.00 AC: 0 AN: 83274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 981332

Other (OTH) AF: 0.00 AC: 0 AN: 55704

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.8
DANN	Benign	0.66
PhyloP100		1.0
PromoterAI		-0.032	Neutral

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

Other links and lift over

dbSNP: rs114432116; hg19: chr4-93225925;