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GeneBe

rs41282782

chr20-46045083-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_020708.5(SLC12A5):c.1512G>A(p.Thr504=) 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

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.24
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.67).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 20-46045083-G-A is Benign according to our data. Variant chr20-46045083-G-A is described in ClinVar as [Benign]. Clinvar id is 475642.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-2.24 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
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 male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 209 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC12A5NM_020708.5 linkuse as main transcriptc.1512G>A p.Thr504= synonymous_variant 12/26 ENST00000243964.7
SLC12A5NM_001134771.2 linkuse as main transcriptc.1581G>A p.Thr527= synonymous_variant 12/26

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC12A5ENST00000243964.7 linkuse as main transcriptc.1512G>A p.Thr504= synonymous_variant 12/261 NM_020708.5 A1Q9H2X9-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0483
AC:
7357
AN:
152186
Hom.:
209
Cov.:
32
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
GnomAD3 exomes
AF:
0.0398
AC:
9925
AN:
249152
Hom.:
270
AF XY:
0.0393
AC XY:
5298
AN XY:
134656
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 SAS exome
AF:
0.00441
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.:
31
AF XY:
0.0445
AC XY:
32354
AN XY:
726302
show subpopulations
Gnomad4 AFR exome
AF:
0.0462
Gnomad4 AMR exome
AF:
0.0305
Gnomad4 ASJ exome
AF:
0.0552
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.00409
Gnomad4 FIN exome
AF:
0.0922
Gnomad4 NFE exome
AF:
0.0492
Gnomad4 OTH exome
AF:
0.0411
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0483
AC:
7357
AN:
152304
Hom.:
209
Cov.:
32
AF XY:
0.0495
AC XY:
3684
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.0454
Gnomad4 AMR
AF:
0.0428
Gnomad4 ASJ
AF:
0.0571
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00539
Gnomad4 FIN
AF:
0.0966
Gnomad4 NFE
AF:
0.0495
Gnomad4 OTH
AF:
0.0483
Alfa
AF:
0.0480
Hom.:
87
Bravo
AF:
0.0444
Asia WGS
AF:
0.00722
AC:
25
AN:
3478
EpiCase
AF:
0.0442
EpiControl
AF:
0.0440

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 34 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.67
Cadd
Benign
3.8
Dann
Benign
0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41282782; hg19: chr20-44673722; COSMIC: COSV54793784; COSMIC: COSV54793784; API