dbSNP rs41282782: SLC12A5:p.Thr504Thr (chr20-46045083-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020708.5(SLC12A5):c.1512G>A(p.Thr504Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0461 in 1,612,380 control chromosomes in the GnomAD database, including 1,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.048 ( 209 hom., cov: 32)

Exomes 𝑓: 0.046 ( 1762 hom. )

Consequence

SLC12A5
NM_020708.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.24

Publications

6 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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina
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: Ambry Genetics, PanelApp Australia, Illumina
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

SLC12A5 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_020708.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 20-46045083-G-A is Benign according to our data. Variant chr20-46045083-G-A is described in ClinVar as Benign. ClinVar VariationId is 475642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.24 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0483 (7357/152304) while in subpopulation NFE AF = 0.0495 (3365/68020). AF 95% confidence interval is 0.0481. There are 209 homozygotes in GnomAd4. There are 3684 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 209 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020708.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	NM_020708.5	MANE Select	c.1512G>A	p.Thr504Thr	synonymous	Exon 12 of 26	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.1581G>A	p.Thr527Thr	synonymous	Exon 12 of 26	NP_001128243.1	Q9H2X9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC12A5	ENST00000243964.7	TSL:1 MANE Select	c.1512G>A	p.Thr504Thr	synonymous	Exon 12 of 26	ENSP00000243964.4	Q9H2X9-2
SLC12A5	ENST00000616202.4	TSL:1	c.612+7698G>A		intron	N/A	ENSP00000478369.1	M4PM71
SLC12A5	ENST00000626937.2	TSL:1	c.509+7801G>A		intron	N/A	ENSP00000485953.1	M4PNC0

Frequencies

GnomAD3 genomes

AF:

0.0483

AC:

7357

AN:

152186

Hom.:

209

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0455

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0429

Gnomad ASJ

AF:

0.0571

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.0966

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0495

Gnomad OTH

AF:

0.0488

GnomAD2 exomes

AF:

0.0398

AC:

9925

AN:

249152

AF XY:

0.0393

show subpopulations

Gnomad AFR exome

AF:

0.0413

Gnomad AMR exome

AF:

0.0283

Gnomad ASJ exome

AF:

0.0540

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0963

Gnomad NFE exome

AF:

0.0471

Gnomad OTH exome

AF:

0.0444

GnomAD4 exome

AF:

0.0459

AC:

66997

AN:

1460076

Hom.:

1762

Cov.:

AF XY:

0.0445

AC XY:

32354

AN XY:

726302

show subpopulations

African (AFR)

AF:

0.0462

AC:

1546

AN:

33450

American (AMR)

AF:

0.0305

AC:

1357

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.0552

AC:

1435

AN:

26018

East Asian (EAS)

AF:

0.000151

AC:

AN:

39674

South Asian (SAS)

AF:

0.00409

AC:

352

AN:

86074

European-Finnish (FIN)

AF:

0.0922

AC:

4883

AN:

52966

Middle Eastern (MID)

AF:

0.0483

AC:

278

AN:

5758

European-Non Finnish (NFE)

AF:

0.0492

AC:

54661

AN:

1111236

Other (OTH)

AF:

0.0411

AC:

2479

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

3707

7413

11120

14826

18533

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2060

4120

6180

8240

10300

<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:

0.0483

AC:

7357

AN:

152304

Hom.:

209

Cov.:

AF XY:

0.0495

AC XY:

3684

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0454

AC:

1888

AN:

41556

American (AMR)

AF:

0.0428

AC:

656

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0571

AC:

198

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00539

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0966

AC:

1026

AN:

10624

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0495

AC:

3365

AN:

68020

Other (OTH)

AF:

0.0483

AC:

102

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

378

756

1134

1512

1890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0479

Hom.:

Bravo

AF:

0.0444

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0442

EpiControl

AF:

0.0440

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 34 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

3.8

(source)

DANN

Benign

0.55

PhyloP100

-2.2

Mutation Taster

=99/1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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