rs767708918
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_ModeratePM2BP6BS1
The NM_020708.5(SLC12A5):c.3126-3dupC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,613,988 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00044 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
SLC12A5
NM_020708.5 splice_acceptor, intron
NM_020708.5 splice_acceptor, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.48
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.039988063 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.4, offset of 0 (no position change), new splice context is: ctcctccttcctgccgccAGgaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 20-46057166-G-GC is Benign according to our data. Variant chr20-46057166-G-GC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542328.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00044 (67/152264) while in subpopulation AFR AF= 0.00152 (63/41556). AF 95% confidence interval is 0.00122. There are 1 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SLC12A5 | NM_020708.5 | c.3126-3dupC | splice_acceptor_variant, intron_variant | Intron 24 of 25 | ENST00000243964.7 | NP_065759.1 | ||
| SLC12A5 | NM_001134771.2 | c.3195-3dupC | splice_acceptor_variant, intron_variant | Intron 24 of 25 | NP_001128243.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000434 AC: 66AN: 152146Hom.: 1 Cov.: 32
GnomAD3 genomes
AF:
AC:
66
AN:
152146
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000112 AC: 28AN: 250824Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135770
GnomAD3 exomes
AF:
AC:
28
AN:
250824
Hom.:
AF XY:
AC XY:
14
AN XY:
135770
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461724Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727146
GnomAD4 exome
AF:
AC:
46
AN:
1461724
Hom.:
Cov.:
31
AF XY:
AC XY:
19
AN XY:
727146
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000440 AC: 67AN: 152264Hom.: 1 Cov.: 32 AF XY: 0.000376 AC XY: 28AN XY: 74448
GnomAD4 genome
AF:
AC:
67
AN:
152264
Hom.:
Cov.:
32
AF XY:
AC XY:
28
AN XY:
74448
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Jun 30, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Unlikely to be causative of SLC12A5-related epilepsy (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Developmental and epileptic encephalopathy, 34 Benign:1
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
SLC12A5-related disorder Benign:1
Dec 19, 2022
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at