11-35315089-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1PM2PP3_StrongPP5_Moderate

The NM_004171.4(SLC1A2):c.244G>A(p.Gly82Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC1A2
NM_004171.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 7.87

Publications

12 publications found

Variant links:

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

SLC1A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS1

Transcript NM_004171.4 (SLC1A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 11-35315089-C-T is Pathogenic according to our data. Variant chr11-35315089-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 438736.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC1A2	NM_004171.4 link	c.244G>A	p.Gly82Arg	missense_variant	Exon 3 of 11	ENST00000278379.9	NP_004162.2	P43004-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC1A2	ENST00000278379.9 link	c.244G>A	p.Gly82Arg	missense_variant	Exon 3 of 11	1	NM_004171.4	ENSP00000278379.3		P43004-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460352

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726590

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110632

Other (OTH)

AF:

0.00

AC:

AN:

60340

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 41

Pathogenic:2

Nov 19, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 08, 2002

Center of Excellence for Medical Genomics, Chulalongkorn University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:1

Feb 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 82 of the SLC1A2 protein (p.Gly82Arg). ClinVar contains an entry for this variant (Variation ID: 438736). This missense change has been observed in individual(s) with SLC1A2-related conditions (PMID: 28777935, 31164858, 31618753). In at least one individual the variant was observed to be de novo. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;.;D;D;D;.;D;.;.;.;.;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

4.1

H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;H;.;.;.;.;.;.;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.96

PROVEAN

Pathogenic

-7.3

D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.

Polyphen

1.0

D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.99

MutPred

0.94

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;Loss of sheet (P = 0.0817);.;.;.;.;.;.;.;.;.;.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;.;.;.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.92

MPC

1.6

ClinPred

1.0

GERP RS

5.7

Varity_R

0.93

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over