Genetic Variant SLC1A2:c.858-106G>A (chr11-35292626-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004171.4(SLC1A2):c.858-106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0887 in 627,598 control chromosomes in the GnomAD database, including 3,117 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 982 hom., cov: 32)

Exomes 𝑓: 0.084 ( 2135 hom. )

Consequence

SLC1A2
NM_004171.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.180

Publications

8 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC1A2	NM_004171.4 link	c.858-106G>A		intron_variant	Intron 6 of 10	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.858-106G>A		intron_variant	Intron 6 of 10	1	NM_004171.4	ENSP00000278379.3		P43004-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15740

AN:

151864

Hom.:

978

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.146

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.190

Gnomad SAS

AF:

0.132

Gnomad FIN

AF:

0.0551

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.0604

Gnomad OTH

AF:

0.121

GnomAD4 exome

AF:

0.0839

AC:

39920

AN:

475616

Hom.:

2135

AF XY:

0.0862

AC XY:

21497

AN XY:

249268

show subpopulations

African (AFR)

AF:

0.151

AC:

1946

AN:

12894

American (AMR)

AF:

0.172

AC:

2676

AN:

15594

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

2114

AN:

13444

East Asian (EAS)

AF:

0.151

AC:

4698

AN:

31034

South Asian (SAS)

AF:

0.133

AC:

5210

AN:

39310

European-Finnish (FIN)

AF:

0.0461

AC:

1487

AN:

32248

Middle Eastern (MID)

AF:

0.212

AC:

746

AN:

3526

European-Non Finnish (NFE)

AF:

0.0612

AC:

18419

AN:

300964

Other (OTH)

AF:

0.0986

AC:

2624

AN:

26602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1743

3487

5230

6974

8717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

314

628

942

1256

1570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.104

AC:

15747

AN:

151982

Hom.:

982

Cov.:

AF XY:

0.104

AC XY:

7710

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.154

AC:

6372

AN:

41458

American (AMR)

AF:

0.146

AC:

2223

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.158

AC:

547

AN:

3470

East Asian (EAS)

AF:

0.190

AC:

984

AN:

5172

South Asian (SAS)

AF:

0.133

AC:

638

AN:

4810

European-Finnish (FIN)

AF:

0.0551

AC:

581

AN:

10540

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0604

AC:

4103

AN:

67952

Other (OTH)

AF:

0.119

AC:

251

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

716

1432

2147

2863

3579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0794

Hom.:

2649

Bravo

AF:

0.115

Asia WGS

AF:

0.154

AC:

538

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

2.6

(source)

DANN

Benign

0.68

PhyloP100

-0.18

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over