chr4-92590127-C-T

Variant names:

• chr4-92590127-C-T
• rs74759637
• NM_001510.4:c.89-4C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS1

The NM_001510.4(GRID2):​c.89-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,603,424 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: GRID2 NM_001510.4 splice_region, intron
• Scores: Splicing: ADA: 0.01253
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.504

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 4-92590127-C-T is Benign according to our data. Variant chr4-92590127-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2086058.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000225 (327/1451198) while in subpopulation MID AF = 0.000696 (4/5746). AF 95% confidence interval is 0.000271. There are 1 homozygotes in GnomAdExome4. There are 180 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRID2	NM_001510.4	c.89-4C>T		splice_region_variant, intron_variant	Intron 1 of 15	ENST00000282020.9	NP_001501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRID2	ENST00000282020.9	c.89-4C>T		splice_region_variant, intron_variant	Intron 1 of 15	1	NM_001510.4	ENSP00000282020.4
GRID2	ENST00000510992.5	c.89-4C>T		splice_region_variant, intron_variant	Intron 1 of 14	1		ENSP00000421257.1
GRID2	ENST00000505687.5	n.261-4C>T		splice_region_variant, intron_variant	Intron 1 of 5	1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000305 AC: 76 AN: 249528 AF XY: 0.000371

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000513

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000225 AC: 327 AN: 1451198 Hom.: 1 Cov.: 28 AF XY: 0.000249 AC XY: 180 AN XY: 722510

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33250

Gnomad4 AMR exome AF: 0.0000225 AC: 1 AN: 44520

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26000

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39578

Gnomad4 SAS exome AF: 0.000373 AC: 32 AN: 85704

Gnomad4 FIN exome AF: 0.000393 AC: 21 AN: 53372

Gnomad4 NFE exome AF: 0.000213 AC: 235 AN: 1103018

Gnomad4 Remaining exome AF: 0.000567 AC: 34 AN: 60010

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74416

Gnomad4 AFR AF: 0.0000481 AC: 0.0000481232 AN: 0.0000481232

Gnomad4 AMR AF: 0.0000654 AC: 0.0000654279 AN: 0.0000654279

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000415 AC: 0.000414766 AN: 0.000414766

Gnomad4 FIN AF: 0.0000943 AC: 0.0000943218 AN: 0.0000943218

Gnomad4 NFE AF: 0.000235 AC: 0.000235294 AN: 0.000235294

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.000125

EpiCase AF: 0.000220

EpiControl AF: 0.000358

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	13
DANN	Benign	0.93
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.14
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: rs74759637; hg19: chr4-93511278;