rs1042113

Variant names:

• chr11-35286822-T-C
• rs1042113
• NM_004171.4:c.1221A>G

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.1221A>G​(p.Val407Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,612,998 control chromosomes in the GnomAD database, including 50,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5243 hom., cov: 32)
  • Exomes 𝑓: 0.25 (45305 hom.)
• Consequence: SLC1A2 NM_004171.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.513
• Publications: 27 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=-0.52).
• BP6: Variant 11-35286822-T-C is Benign according to our data. Variant chr11-35286822-T-C is described in ClinVar as Benign. ClinVar VariationId is 1165045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.513 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.292 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.1221A>G	p.Val407Val	synonymous	Exon 8 of 11	NP_004162.2
	SLC1A2	NM_001439342.1		c.1209A>G	p.Val403Val	synonymous	Exon 8 of 11	NP_001426271.1
	SLC1A2	NM_001195728.3		c.1194A>G	p.Val398Val	synonymous	Exon 9 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.1221A>G	p.Val407Val	synonymous	Exon 8 of 11	ENSP00000278379.3	P43004-1
	SLC1A2	ENST00000395750.6	TSL:1	c.1209A>G	p.Val403Val	synonymous	Exon 8 of 11	ENSP00000379099.2	A0A2U3TZS7
	SLC1A2	ENST00000644779.1		c.1332A>G	p.Val444Val	synonymous	Exon 11 of 14	ENSP00000494258.1	A0A2R8YD46

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39258 AN: 151928 Hom.: 5221 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.0996

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.244 AC: 61384 AN: 251244 AF XY: 0.235

Gnomad AFR exome AF: 0.282

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.202

Gnomad FIN exome AF: 0.323

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.254

GnomAD4 exome AF: 0.245 AC: 358436 AN: 1460954 Hom.: 45305 Cov.: 33 AF XY: 0.241 AC XY: 174832 AN XY: 726820

African (AFR) AF: 0.283 AC: 9454 AN: 33448

American (AMR) AF: 0.304 AC: 13597 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 5500 AN: 26122

East Asian (EAS) AF: 0.268 AC: 10629 AN: 39686

South Asian (SAS) AF: 0.114 AC: 9796 AN: 86224

European-Finnish (FIN) AF: 0.319 AC: 17021 AN: 53420

Middle Eastern (MID) AF: 0.200 AC: 1153 AN: 5752

European-Non Finnish (NFE) AF: 0.249 AC: 277185 AN: 1111244

Other (OTH) AF: 0.234 AC: 14101 AN: 60350

GnomAD4 genome AF: 0.259 AC: 39321 AN: 152044 Hom.: 5243 Cov.: 32 AF XY: 0.259 AC XY: 19220 AN XY: 74294

African (AFR) AF: 0.274 AC: 11381 AN: 41470

American (AMR) AF: 0.299 AC: 4573 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 708 AN: 3468

East Asian (EAS) AF: 0.210 AC: 1084 AN: 5168

South Asian (SAS) AF: 0.0989 AC: 476 AN: 4814

European-Finnish (FIN) AF: 0.318 AC: 3357 AN: 10560

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16967 AN: 67976

Other (OTH) AF: 0.243 AC: 513 AN: 2108

Alfa AF: 0.248 Hom.: 6207

Bravo AF: 0.260

Asia WGS AF: 0.201 AC: 697 AN: 3478

EpiCase AF: 0.246

EpiControl AF: 0.248

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy, 41 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.7
DANN	Benign	0.63
PhyloP100		0.51
PromoterAI		0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=84/16	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: rs1042113; hg19: chr11-35308369; COSMIC: COSV53518798; COSMIC: COSV53518798;