rs2273689

Variant names:

• chr11-35301653-A-G
• rs2273689
• NM_004171.4:c.731-8T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-35301653-A-G
• chr11-35301653-A-C

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.0001068
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.401
• Publications: 15 publications found

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]

SLC1A2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 41

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004171.4. 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
	SLC1A2	NM_004171.4	MANE Select	c.731-8T>C		splice_region intron	N/A	NP_004162.2
	SLC1A2	NM_001439342.1		c.719-8T>C		splice_region intron	N/A	NP_001426271.1
	SLC1A2	NM_001195728.3		c.704-8T>C		splice_region intron	N/A	NP_001182657.1	P43004-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A2	ENST00000278379.9	TSL:1 MANE Select	c.731-8T>C		splice_region intron	N/A	ENSP00000278379.3	P43004-1
	SLC1A2	ENST00000395750.6	TSL:1	c.719-8T>C		splice_region intron	N/A	ENSP00000379099.2	A0A2U3TZS7
	SLC1A2	ENST00000644779.1		c.842-8T>C		splice_region intron	N/A	ENSP00000494258.1	A0A2R8YD46

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

GnomAD2 exomes AF: 0.640 AC: 159643 AN: 249370 AF XY: 0.646

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 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

African (AFR) AF: 0.298 AC: 9937 AN: 33376

American (AMR) AF: 0.639 AC: 28471 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 17769 AN: 26098

East Asian (EAS) AF: 0.780 AC: 30934 AN: 39652

South Asian (SAS) AF: 0.651 AC: 56011 AN: 86034

European-Finnish (FIN) AF: 0.678 AC: 35994 AN: 53078

Middle Eastern (MID) AF: 0.610 AC: 3513 AN: 5756

European-Non Finnish (NFE) AF: 0.649 AC: 720244 AN: 1110078

Other (OTH) AF: 0.630 AC: 37966 AN: 60272

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

African (AFR) AF: 0.300 AC: 12451 AN: 41482

American (AMR) AF: 0.639 AC: 9774 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2393 AN: 3468

East Asian (EAS) AF: 0.737 AC: 3819 AN: 5180

South Asian (SAS) AF: 0.653 AC: 3147 AN: 4818

European-Finnish (FIN) AF: 0.667 AC: 7066 AN: 10588

Middle Eastern (MID) AF: 0.671 AC: 196 AN: 292

European-Non Finnish (NFE) AF: 0.653 AC: 44393 AN: 67980

Other (OTH) AF: 0.597 AC: 1264 AN: 2116

Alfa AF: 0.622 Hom.: 24621

Bravo AF: 0.546

Asia WGS AF: 0.671 AC: 2328 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 41 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.6
DANN	Benign	0.87
PhyloP100		0.40
PromoterAI		-0.0013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2273689; hg19: chr11-35323200; COSMIC: COSV53520549; COSMIC: COSV53520549;