rs752949

Variant names:

• chr11-35306201-C-T
• rs752949
• NM_004171.4:c.603G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-35306201-C-T
• chr11-35306201-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004171.4(SLC1A2):​c.603G>A​(p.Pro201Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,613,208 control chromosomes in the GnomAD database, including 48,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3997 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44378 hom.)
• Consequence: SLC1A2 NM_004171.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.26
• Publications: 34 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-35306201-C-T is Benign according to our data. Variant chr11-35306201-C-T is described in ClinVar as Benign. ClinVar VariationId is 1165046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.275 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.603G>A	p.Pro201Pro	synonymous	Exon 5 of 11	NP_004162.2
	SLC1A2	NM_001439342.1		c.591G>A	p.Pro197Pro	synonymous	Exon 5 of 11	NP_001426271.1
	SLC1A2	NM_001195728.3		c.576G>A	p.Pro192Pro	synonymous	Exon 6 of 12	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.603G>A	p.Pro201Pro	synonymous	Exon 5 of 11	ENSP00000278379.3	P43004-1
	SLC1A2	ENST00000395750.6	TSL:1	c.591G>A	p.Pro197Pro	synonymous	Exon 5 of 11	ENSP00000379099.2	A0A2U3TZS7
	SLC1A2	ENST00000644779.1		c.714G>A	p.Pro238Pro	synonymous	Exon 8 of 14	ENSP00000494258.1	A0A2R8YD46

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33297 AN: 151812 Hom.: 3980 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.0918

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.233 AC: 58560 AN: 251040 AF XY: 0.227

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.208

Gnomad FIN exome AF: 0.324

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.250

GnomAD4 exome AF: 0.242 AC: 353646 AN: 1461278 Hom.: 44378 Cov.: 33 AF XY: 0.237 AC XY: 172605 AN XY: 726972

African (AFR) AF: 0.138 AC: 4629 AN: 33460

American (AMR) AF: 0.292 AC: 13045 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5533 AN: 26122

East Asian (EAS) AF: 0.273 AC: 10828 AN: 39690

South Asian (SAS) AF: 0.103 AC: 8892 AN: 86232

European-Finnish (FIN) AF: 0.319 AC: 17046 AN: 53380

Middle Eastern (MID) AF: 0.192 AC: 1105 AN: 5766

European-Non Finnish (NFE) AF: 0.251 AC: 279088 AN: 1111548

Other (OTH) AF: 0.223 AC: 13480 AN: 60374

GnomAD4 genome AF: 0.219 AC: 33343 AN: 151930 Hom.: 3997 Cov.: 32 AF XY: 0.221 AC XY: 16406 AN XY: 74244

African (AFR) AF: 0.136 AC: 5643 AN: 41432

American (AMR) AF: 0.282 AC: 4301 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 712 AN: 3468

East Asian (EAS) AF: 0.214 AC: 1106 AN: 5166

South Asian (SAS) AF: 0.0910 AC: 438 AN: 4812

European-Finnish (FIN) AF: 0.320 AC: 3364 AN: 10526

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17050 AN: 67982

Other (OTH) AF: 0.221 AC: 465 AN: 2108

Alfa AF: 0.238 Hom.: 20060

Bravo AF: 0.217

Asia WGS AF: 0.186 AC: 647 AN: 3476

EpiCase AF: 0.247

EpiControl AF: 0.250

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	-0.79
CADD	Benign	3.7
DANN	Benign	0.65
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs752949; hg19: chr11-35327748; COSMIC: COSV53519625; COSMIC: COSV53519625;