20-46021881-T-A

Variant names:

• chr20-46021881-T-A
• rs759067394
• NM_001134771.2:c.116T>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_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. 14/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.101

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)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. 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
SLC12A5	NM_001134771.2	c.116T>A	p.Val39Asp	missense_variant	Exon 1 of 26		NP_001128243.1
SLC12A5-AS1	NR_147699.1	n.193A>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000454036.6	c.116T>A	p.Val39Asp	missense_variant	Exon 1 of 26	5		ENSP00000387694.1
SLC12A5	ENST00000626701.1	c.116T>A	p.Val39Asp	missense_variant	Exon 1 of 3	3		ENSP00000487372.1
SLC12A5	ENST00000413737.2	c.41T>A	p.Val14Asp	missense_variant	Exon 1 of 3	3		ENSP00000487291.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151700 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000244 AC: 3 AN: 123158 AF XY: 0.0000441

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 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

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 30086

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 35132

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24714

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 34704

Gnomad4 SAS exome AF: 0.000153 AC: 12 AN: 78386

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 34430

Gnomad4 NFE exome AF: 0.0000102 AC: 11 AN: 1074988

Gnomad4 Remaining exome AF: 0.0000349 AC: 2 AN: 57364

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151812 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74208

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000623 AC: 0.000623441 AN: 0.000623441

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000601 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 34 Uncertain:1

Nov 10, 2023

Daryl Scott Lab, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
Mutation Taster		=92/8	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs759067394; hg19: chr20-44650520;