rs143969641

Positions:

• chr20-46034991-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020708.5(SLC12A5):​c.96C>T​(p.Thr32=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,613,968 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (20 hom.)
• Consequence: SLC12A5 NM_020708.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -8.14

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 20-46034991-C-T is Benign according to our data. Variant chr20-46034991-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 542322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46034991-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-8.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00208 (316/152154) while in subpopulation NFE AF= 0.00363 (247/67982). AF 95% confidence interval is 0.00326. There are 3 homozygotes in gnomad4. There are 136 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A5	NM_020708.5	c.96C>T	p.Thr32=	synonymous_variant	2/26	ENST00000243964.7
SLC12A5	NM_001134771.2	c.165C>T	p.Thr55=	synonymous_variant	2/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A5	ENST00000243964.7	c.96C>T	p.Thr32=	synonymous_variant	2/26	1	NM_020708.5	A1

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152036 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.00251 AC: 630 AN: 251462 Hom.: 3 AF XY: 0.00261 AC XY: 355 AN XY: 135902

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00353

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00363

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00328 AC: 4798 AN: 1461814 Hom.: 20 Cov.: 32 AF XY: 0.00320 AC XY: 2328 AN XY: 727220

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00312

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.00376

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00208 AC: 316 AN: 152154 Hom.: 3 Cov.: 31 AF XY: 0.00183 AC XY: 136 AN XY: 74384

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.00308 Hom.: 1

Bravo AF: 0.00188

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SLC12A5: BP4, BP7, BS2 -

Developmental and epileptic encephalopathy, 34 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.56
DANN	Benign	0.64

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

Other links and lift over

dbSNP: rs143969641; hg19: chr20-44663630;