NM_004171.4:c.311-37A>G

Variant names:

• chr11-35312485-T-C
• rs10836370
• NM_004171.4:c.311-37A>G

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.311-37A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,606,604 control chromosomes in the GnomAD database, including 44,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3777 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41044 hom.)
• Consequence: SLC1A2 NM_004171.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.116
• Publications: 5 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: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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=-0.82).
• BP6: Variant 11-35312485-T-C is Benign according to our data. Variant chr11-35312485-T-C is described in ClinVar as Benign. ClinVar VariationId is 1332977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A2	NM_004171.4	MANE Select	c.311-37A>G		intron	N/A	NP_004162.2
	SLC1A2	NM_001439342.1		c.299-37A>G		intron	N/A	NP_001426271.1
	SLC1A2	NM_001195728.3		c.284-37A>G		intron	N/A	NP_001182657.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A2	ENST00000278379.9	TSL:1 MANE Select	c.311-37A>G		intron	N/A	ENSP00000278379.3
	SLC1A2	ENST00000395750.6	TSL:1	c.299-37A>G		intron	N/A	ENSP00000379099.2
	SLC1A2	ENST00000644779.1		c.422-37A>G		intron	N/A	ENSP00000494258.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31962 AN: 152112 Hom.: 3757 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.208

GnomAD2 exomes AF: 0.235 AC: 58197 AN: 248162 AF XY: 0.229

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.300

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.232 AC: 337931 AN: 1454374 Hom.: 41044 Cov.: 31 AF XY: 0.229 AC XY: 165735 AN XY: 723010

African (AFR) AF: 0.109 AC: 3642 AN: 33348

American (AMR) AF: 0.288 AC: 12862 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 7157 AN: 26028

East Asian (EAS) AF: 0.379 AC: 14995 AN: 39524

South Asian (SAS) AF: 0.126 AC: 10873 AN: 86072

European-Finnish (FIN) AF: 0.279 AC: 14902 AN: 53336

Middle Eastern (MID) AF: 0.222 AC: 1258 AN: 5668

European-Non Finnish (NFE) AF: 0.234 AC: 258834 AN: 1105706

Other (OTH) AF: 0.223 AC: 13408 AN: 60092

GnomAD4 genome AF: 0.210 AC: 32009 AN: 152230 Hom.: 3777 Cov.: 32 AF XY: 0.212 AC XY: 15799 AN XY: 74422

African (AFR) AF: 0.113 AC: 4681 AN: 41560

American (AMR) AF: 0.274 AC: 4196 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 921 AN: 3472

East Asian (EAS) AF: 0.308 AC: 1592 AN: 5164

South Asian (SAS) AF: 0.120 AC: 577 AN: 4826

European-Finnish (FIN) AF: 0.290 AC: 3072 AN: 10588

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

European-Non Finnish (NFE) AF: 0.239 AC: 16250 AN: 68004

Other (OTH) AF: 0.216 AC: 457 AN: 2114

Alfa AF: 0.228 Hom.: 3303

Bravo AF: 0.207

Asia WGS AF: 0.256 AC: 890 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.7
DANN	Benign	0.45
PhyloP100		0.12
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: rs10836370; hg19: chr11-35334032; COSMIC: COSV107209865; COSMIC: COSV107209865;