4-92304667-T-C

Position:

• chr4-92304667-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001510.4(GRID2):​c.11T>C​(p.Phe4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict 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: 0.0000034 (0 hom.)
• Consequence: GRID2 NM_001510.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRID2	NM_001510.4	c.11T>C	p.Phe4Ser	missense_variant	1/16	ENST00000282020.9	NP_001501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRID2	ENST00000282020.9	c.11T>C	p.Phe4Ser	missense_variant	1/16	1	NM_001510.4	ENSP00000282020.4
GRID2	ENST00000510992.5	c.11T>C	p.Phe4Ser	missense_variant	1/15	1		ENSP00000421257.1
GRID2	ENST00000505687.5	n.183T>C		non_coding_transcript_exon_variant	1/6	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460294 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726608

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2024

The c.11T>C (p.F4S) alteration is located in exon 1 (coding exon 1) of the GRID2 gene. This alteration results from a T to C substitution at nucleotide position 11, causing the phenylalanine (F) at amino acid position 4 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.24	N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;.
Vest4		0.66
MutPred		0.77		Gain of disorder (P = 4e-04);Gain of disorder (P = 4e-04);
MVP		0.73
MPC		0.38
ClinPred		0.42	T
GERP RS		3.4
Varity_R		0.37
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-93225818;