20-46021881-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001134771.2(SLC12A5):​c.116T>A​(p.Val39Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000203 in 1,525,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V39F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

SLC12A5
NM_001134771.2 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.101
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-AS1 (HGNC:53143): (SLC12A5 and MMP9 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06526315).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000198 (3/151812) while in subpopulation SAS AF= 0.000623 (3/4812). AF 95% confidence interval is 0.000169. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC12A5NM_001134771.2 linkc.116T>A p.Val39Asp missense_variant Exon 1 of 26 NP_001128243.1 Q9H2X9-1
SLC12A5-AS1NR_147699.1 linkn.193A>T non_coding_transcript_exon_variant Exon 1 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC12A5ENST00000454036.6 linkc.116T>A p.Val39Asp missense_variant Exon 1 of 26 5 ENSP00000387694.1 Q9H2X9-1
SLC12A5ENST00000626701.1 linkc.116T>A p.Val39Asp missense_variant Exon 1 of 3 3 ENSP00000487372.1 A0A0D9SGD0
SLC12A5ENST00000413737.2 linkc.41T>A p.Val14Asp missense_variant Exon 1 of 3 3 ENSP00000487291.1 A0A0D9SGA5

Frequencies

GnomAD3 genomes
AF:
0.0000198
AC:
3
AN:
151700
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000623
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000244
AC:
3
AN:
123158
Hom.:
0
AF XY:
0.0000441
AC XY:
3
AN XY:
68004
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000139
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000204
AC:
28
AN:
1374012
Hom.:
0
Cov.:
32
AF XY:
0.0000251
AC XY:
17
AN XY:
677892
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000153
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000102
Gnomad4 OTH exome
AF:
0.0000349
GnomAD4 genome
AF:
0.0000198
AC:
3
AN:
151812
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74208
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000623
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000601
AC:
3

ClinVar

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

Submissions by phenotype

Developmental and epileptic encephalopathy, 34 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingDaryl Scott Lab, Baylor College of MedicineNov 10, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
19
DANN
Benign
0.94
DEOGEN2
Benign
0.063
T;.;T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.097
N
LIST_S2
Benign
0.32
T;T;T
M_CAP
Pathogenic
0.36
D
MetaRNN
Benign
0.065
T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
-0.34
N;.;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
0.42
N;.;.
REVEL
Benign
0.17
Sift
Benign
0.23
T;.;.
Sift4G
Benign
0.62
T;D;T
Polyphen
0.0
B;.;.
Vest4
0.23
MutPred
0.15
Loss of methylation at K40 (P = 0.0379);Loss of methylation at K40 (P = 0.0379);Loss of methylation at K40 (P = 0.0379);
MVP
0.30
MPC
1.5
ClinPred
0.065
T
GERP RS
0.51
Varity_R
0.087
gMVP
0.49

Splicing

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: rs759067394; hg19: chr20-44650520; API