NM_020708.5:c.2012+3T>A

Variant names:

Variant summary

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

The NM_020708.5(SLC12A5):c.2012+3T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,608,780 control chromosomes in the GnomAD database, including 1,049 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 0.030 ( 164 hom., cov: 31)

Exomes 𝑓: 0.027 ( 885 hom. )

Consequence

SLC12A5
NM_020708.5 splice_region, intron

Scores

Splicing: ADA: 0.00005421

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.946

Publications

8 publications found

Variant links:

Genes affected

SLC12A5 (HGNC:13818): (solute carrier family 12 member 5) K-Cl cotransporters are proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The protein encoded by this gene is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Sep 2008]

SLC12A5 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 34
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
epilepsy of infancy with migrating focal seizures
Inheritance: AR Classification: STRONG Submitted by: G2P
malignant migrating partial seizures of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy, idiopathic generalized, susceptibility to, 14
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Ambry Genetics
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

SLC12A5 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=-0.75).

BP6

Variant 20-46048088-T-A is Benign according to our data. Variant chr20-46048088-T-A is described in ClinVar as Benign. ClinVar VariationId is 475644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5 link	c.2012+3T>A		splice_region_variant, intron_variant	Intron 16 of 25	ENST00000243964.7	NP_065759.1	Q9H2X9-2
SLC12A5	NM_001134771.2 link	c.2081+3T>A		splice_region_variant, intron_variant	Intron 16 of 25		NP_001128243.1	Q9H2X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7 link	c.2012+3T>A		splice_region_variant, intron_variant	Intron 16 of 25	1	NM_020708.5	ENSP00000243964.4		Q9H2X9-2

Frequencies

GnomAD3 genomes

AF:

0.0303

AC:

4597

AN:

151894

Hom.:

162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0143

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.111

Gnomad ASJ

AF:

0.0530

Gnomad EAS

AF:

0.0249

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.0190

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0230

Gnomad OTH

AF:

0.0364

GnomAD2 exomes

AF:

0.0396

AC:

9514

AN:

240124

AF XY:

0.0363

show subpopulations

Gnomad AFR exome

AF:

0.0128

Gnomad AMR exome

AF:

0.128

Gnomad ASJ exome

AF:

0.0497

Gnomad EAS exome

AF:

0.0341

Gnomad FIN exome

AF:

0.0224

Gnomad NFE exome

AF:

0.0219

Gnomad OTH exome

AF:

0.0378

GnomAD4 exome

AF:

0.0272

AC:

39618

AN:

1456768

Hom.:

885

Cov.:

AF XY:

0.0270

AC XY:

19522

AN XY:

724060

show subpopulations

African (AFR)

AF:

0.0125

AC:

417

AN:

33426

American (AMR)

AF:

0.128

AC:

5605

AN:

43954

Ashkenazi Jewish (ASJ)

AF:

0.0517

AC:

1343

AN:

25962

East Asian (EAS)

AF:

0.0231

AC:

915

AN:

39612

South Asian (SAS)

AF:

0.0299

AC:

2553

AN:

85256

European-Finnish (FIN)

AF:

0.0197

AC:

1046

AN:

53126

Middle Eastern (MID)

AF:

0.0151

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0233

AC:

25798

AN:

1109512

Other (OTH)

AF:

0.0308

AC:

1854

AN:

60164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

1973

3945

5918

7890

9863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1078

2156

3234

4312

5390

<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:

0.0303

AC:

4606

AN:

152012

Hom.:

164

Cov.:

AF XY:

0.0320

AC XY:

2381

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0143

AC:

594

AN:

41454

American (AMR)

AF:

0.111

AC:

1694

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0530

AC:

184

AN:

3470

East Asian (EAS)

AF:

0.0252

AC:

130

AN:

5160

South Asian (SAS)

AF:

0.0261

AC:

125

AN:

4788

European-Finnish (FIN)

AF:

0.0190

AC:

202

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0229

AC:

1559

AN:

67942

Other (OTH)

AF:

0.0370

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

211

422

634

845

1056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0256

Hom.:

Bravo

AF:

0.0354

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 34

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.051

(source)

DANN

Benign

0.70

PhyloP100

-0.95

Mutation Taster

=57/43

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000054

dbscSNV1_RF

Benign

0.070

SpliceAI score (max)

0.010

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