Variant 20-46021881-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001134771.2(SLC12A5):c.116T>C(p.Val39Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000291 in 1,374,012 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

SLC12A5
NM_001134771.2 missense

Scores

Clinical Significance

Not reported in ClinVar

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 links:

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

SLC12A5-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062082887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_001134771.2 link	c.116T>C	p.Val39Ala	missense_variant	Exon 1 of 26		NP_001128243.1	Q9H2X9-1
SLC12A5-AS1	NR_147699.1 link	n.193A>G		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
SLC12A5	ENST00000454036.6 link	c.116T>C	p.Val39Ala	missense_variant	Exon 1 of 26	5	ENSP00000387694.1	Q9H2X9-1
SLC12A5	ENST00000626701.1 link	c.116T>C	p.Val39Ala	missense_variant	Exon 1 of 3	3	ENSP00000487372.1	A0A0D9SGD0
SLC12A5	ENST00000413737.2 link	c.41T>C	p.Val14Ala	missense_variant	Exon 1 of 3	3	ENSP00000487291.1	A0A0D9SGA5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000812

AC:

AN:

123158

Hom.:

AF XY:

0.0000147

AC XY:

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:

0.0000463

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000291

AC:

AN:

1374012

Hom.:

Cov.:

AF XY:

0.00000590

AC XY:

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:

0.0000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000279

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.062

T;.;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.082

T;T;T

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.062

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

N;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.86

N;.;.

REVEL

Benign

0.16

Sift

Benign

0.67

T;.;.

Sift4G

Benign

0.79

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.039

MutPred

0.16

Loss of methylation at K40 (P = 0.0407);Loss of methylation at K40 (P = 0.0407);Loss of methylation at K40 (P = 0.0407);

MVP

0.30

MPC

1.1

ClinPred

0.081

GERP RS

0.51

Varity_R

0.030

gMVP

0.33

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over