NM_004171.4:c.731-8T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004171.4(SLC1A2):c.731-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,611,004 control chromosomes in the GnomAD database, including 332,185 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 25817 hom., cov: 32)

Exomes 𝑓: 0.64 ( 306368 hom. )

Consequence

SLC1A2
NM_004171.4 splice_region, intron

Scores

Splicing: ADA: 0.0001068

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.401

Publications

15 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 11-35301653-A-G is Benign according to our data. Variant chr11-35301653-A-G is described in ClinVar as Benign. ClinVar VariationId is 1169957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC1A2	NM_004171.4 link	c.731-8T>C		splice_region_variant, intron_variant	Intron 5 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.731-8T>C		splice_region_variant, intron_variant	Intron 5 of 10	1	NM_004171.4	ENSP00000278379.3		P43004-1

Frequencies

GnomAD3 genomes

AF:

0.560

AC:

85113

AN:

152002

Hom.:

25804

Cov.:

show subpopulations

Gnomad AFR

AF:

0.300

Gnomad AMI

AF:

0.720

Gnomad AMR

AF:

0.639

Gnomad ASJ

AF:

0.690

Gnomad EAS

AF:

0.737

Gnomad SAS

AF:

0.652

Gnomad FIN

AF:

0.667

Gnomad MID

AF:

0.678

Gnomad NFE

AF:

0.653

Gnomad OTH

AF:

0.593

GnomAD2 exomes

AF:

0.640

AC:

159643

AN:

249370

AF XY:

0.646

show subpopulations

Gnomad AFR exome

AF:

0.293

Gnomad AMR exome

AF:

0.642

Gnomad ASJ exome

AF:

0.679

Gnomad EAS exome

AF:

0.731

Gnomad FIN exome

AF:

0.676

Gnomad NFE exome

AF:

0.660

Gnomad OTH exome

AF:

0.663

GnomAD4 exome

AF:

0.645

AC:

940839

AN:

1458884

Hom.:

306368

Cov.:

AF XY:

0.646

AC XY:

468952

AN XY:

725948

show subpopulations

African (AFR)

AF:

0.298

AC:

9937

AN:

33376

American (AMR)

AF:

0.639

AC:

28471

AN:

44540

Ashkenazi Jewish (ASJ)

AF:

0.681

AC:

17769

AN:

26098

East Asian (EAS)

AF:

0.780

AC:

30934

AN:

39652

South Asian (SAS)

AF:

0.651

AC:

56011

AN:

86034

European-Finnish (FIN)

AF:

0.678

AC:

35994

AN:

53078

Middle Eastern (MID)

AF:

0.610

AC:

3513

AN:

5756

European-Non Finnish (NFE)

AF:

0.649

AC:

720244

AN:

1110078

Other (OTH)

AF:

0.630

AC:

37966

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

14980

29960

44941

59921

74901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18852

37704

56556

75408

94260

<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:

0.560

AC:

85158

AN:

152120

Hom.:

25817

Cov.:

AF XY:

0.569

AC XY:

42304

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.300

AC:

12451

AN:

41482

American (AMR)

AF:

0.639

AC:

9774

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.690

AC:

2393

AN:

3468

East Asian (EAS)

AF:

0.737

AC:

3819

AN:

5180

South Asian (SAS)

AF:

0.653

AC:

3147

AN:

4818

European-Finnish (FIN)

AF:

0.667

AC:

7066

AN:

10588

Middle Eastern (MID)

AF:

0.671

AC:

196

AN:

292

European-Non Finnish (NFE)

AF:

0.653

AC:

44393

AN:

67980

Other (OTH)

AF:

0.597

AC:

1264

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1768

3536

5303

7071

8839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

716

1432

2148

2864

3580

<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:

0.622

Hom.:

24621

Bravo

AF:

0.546

Asia WGS

AF:

0.671

AC:

2328

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 41

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

8.6

(source)

DANN

Benign

0.87

PhyloP100

0.40

PromoterAI

-0.0013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.044

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over