11-35301653-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004171.4(SLC1A2):c.731-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,611,004 control chromosomes in the GnomAD database, including 332,185 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25817 hom., cov: 32)
  • Exomes 𝑓: 0.64 (306368 hom.)
• Consequence: SLC1A2 NM_004171.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001068
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.401

Genes affected

SLC1A2 (HGNC:10940): (solute carrier family 1 member 2) This gene encodes a member of a family of solute transporter proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. Improper regulation of this gene is thought to be associated with several neurological disorders. Alternatively spliced transcript variants of this gene have been identified. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 11-35301653-A-G is Benign according to our data. Variant chr11-35301653-A-G is described in ClinVar as [Benign]. Clinvar id is 1169957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A2	NM_004171.4	c.731-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000278379.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A2	ENST00000278379.9	c.731-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004171.4	P4

Frequencies

GnomAD3 genomes AF: 0.560 AC: 85113 AN: 152002 Hom.: 25804 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.639

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.678

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.593

GnomAD3 exomes AF: 0.640 AC: 159643 AN: 249370 Hom.: 52223 AF XY: 0.646 AC XY: 87182 AN XY: 134862

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.642

Gnomad ASJ exome AF: 0.679

Gnomad EAS exome AF: 0.731

Gnomad SAS exome AF: 0.651

Gnomad FIN exome AF: 0.676

Gnomad NFE exome AF: 0.660

Gnomad OTH exome AF: 0.663

GnomAD4 exome AF: 0.645 AC: 940839 AN: 1458884 Hom.: 306368 Cov.: 34 AF XY: 0.646 AC XY: 468952 AN XY: 725948

Gnomad4 AFR exome AF: 0.298

Gnomad4 AMR exome AF: 0.639

Gnomad4 ASJ exome AF: 0.681

Gnomad4 EAS exome AF: 0.780

Gnomad4 SAS exome AF: 0.651

Gnomad4 FIN exome AF: 0.678

Gnomad4 NFE exome AF: 0.649

Gnomad4 OTH exome AF: 0.630

GnomAD4 genome AF: 0.560 AC: 85158 AN: 152120 Hom.: 25817 Cov.: 32 AF XY: 0.569 AC XY: 42304 AN XY: 74368

Gnomad4 AFR AF: 0.300

Gnomad4 AMR AF: 0.639

Gnomad4 ASJ AF: 0.690

Gnomad4 EAS AF: 0.737

Gnomad4 SAS AF: 0.653

Gnomad4 FIN AF: 0.667

Gnomad4 NFE AF: 0.653

Gnomad4 OTH AF: 0.597

Alfa AF: 0.623 Hom.: 23014

Bravo AF: 0.546

Asia WGS AF: 0.671 AC: 2328 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Developmental and epileptic encephalopathy, 41 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	8.6
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.044
SpliceAI score (max)		0.020		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: rs2273689; hg19: chr11-35323200; COSMIC: COSV53520549; COSMIC: COSV53520549;