dbSNP rs56205617: SLC1A2:c.18-5044G>A (chr11-35322560-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_001195728.3(SLC1A2):c.-11+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,516,772 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.033 ( 95 hom., cov: 32)

Exomes 𝑓: 0.029 ( 666 hom. )

Consequence

SLC1A2
NM_001195728.3 splice_donor, intron

Scores

Splicing: ADA: 0.00006553

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.27

Publications

3 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: 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

SLC1A2 links:

Genome browser will be placed here

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=-0.9).

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0661 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195728.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC1A2	NM_004171.4	MANE Select	c.18-5044G>A	intron	N/A	NP_004162.2
SLC1A2	NM_001439342.1		c.6-5044G>A	intron	N/A	NP_001426271.1
SLC1A2	NM_001195728.3		c.-11+1G>A	splice_donor intron	N/A	NP_001182657.1	P43004-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC1A2	ENST00000278379.9	TSL:1 MANE Select	c.18-5044G>A	intron	N/A	ENSP00000278379.3	P43004-1
SLC1A2	ENST00000395750.6	TSL:1	c.6-5044G>A	intron	N/A	ENSP00000379099.2	A0A2U3TZS7
SLC1A2	ENST00000644779.1		c.128+1G>A	splice_donor intron	N/A	ENSP00000494258.1	A0A2R8YD46

Frequencies

GnomAD3 genomes

AF:

0.0333

AC:

5063

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0433

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.0285

Gnomad ASJ

AF:

0.0499

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.0260

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0313

Gnomad OTH

AF:

0.0377

GnomAD2 exomes

AF:

0.0263

AC:

3368

AN:

127894

AF XY:

0.0260

show subpopulations

Gnomad AFR exome

AF:

0.0460

Gnomad AMR exome

AF:

0.0203

Gnomad ASJ exome

AF:

0.0428

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0304

Gnomad NFE exome

AF:

0.0330

Gnomad OTH exome

AF:

0.0377

GnomAD4 exome

AF:

0.0290

AC:

39620

AN:

1364492

Hom.:

666

Cov.:

AF XY:

0.0290

AC XY:

19533

AN XY:

674592

show subpopulations

African (AFR)

AF:

0.0468

AC:

1461

AN:

31196

American (AMR)

AF:

0.0209

AC:

747

AN:

35680

Ashkenazi Jewish (ASJ)

AF:

0.0458

AC:

1148

AN:

25078

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35650

South Asian (SAS)

AF:

0.0162

AC:

1275

AN:

78852

European-Finnish (FIN)

AF:

0.0300

AC:

1002

AN:

33450

Middle Eastern (MID)

AF:

0.0720

AC:

389

AN:

5402

European-Non Finnish (NFE)

AF:

0.0299

AC:

31706

AN:

1061934

Other (OTH)

AF:

0.0330

AC:

1891

AN:

57250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1957

3914

5871

7828

9785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1204

2408

3612

4816

6020

<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:

0.0333

AC:

5065

AN:

152280

Hom.:

Cov.:

AF XY:

0.0327

AC XY:

2434

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0432

AC:

1795

AN:

41552

American (AMR)

AF:

0.0285

AC:

436

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0499

AC:

173

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0147

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0260

AC:

276

AN:

10612

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0313

AC:

2130

AN:

68014

Other (OTH)

AF:

0.0378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

260

520

781

1041

1301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0354

Hom.:

Bravo

AF:

0.0341

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0324

AC:

125

ExAC

AF:

0.0188

AC:

309

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.076

(source)

DANN

Benign

0.42

FATHMM_MKL

Benign

0.0020

PhyloP100

-2.3

GERP RS

-4.7

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000066

dbscSNV1_RF

Benign

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over