rs147042920

chr20-46037250-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_020708.5(SLC12A5):c.482-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00991 in 1,596,084 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (7 hom., cov: 31)
  • Exomes 𝑓: 0.010 (105 hom.)
• Consequence: SLC12A5 NM_020708.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002407
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.827

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 20-46037250-T-C is Benign according to our data. Variant chr20-46037250-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 475657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00666 (1013/152202) while in subpopulation SAS AF= 0.0158 (76/4816). AF 95% confidence interval is 0.0129. There are 7 homozygotes in gnomad4. There are 481 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A5	NM_020708.5	c.482-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000243964.7
SLC12A5	NM_001134771.2	c.551-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A5	ENST00000243964.7	c.482-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_020708.5	A1

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1014 AN: 152084 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00697 AC: 1656 AN: 237704 Hom.: 7 AF XY: 0.00755 AC XY: 969 AN XY: 128322

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00357

Gnomad ASJ exome AF: 0.00662

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.0121

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00936

Gnomad OTH exome AF: 0.00901

GnomAD4 exome AF: 0.0102 AC: 14799 AN: 1443882 Hom.: 105 Cov.: 30 AF XY: 0.0104 AC XY: 7423 AN XY: 716984

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00398

Gnomad4 ASJ exome AF: 0.00659

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0123

Gnomad4 FIN exome AF: 0.00326

Gnomad4 NFE exome AF: 0.0114

Gnomad4 OTH exome AF: 0.0100

GnomAD4 genome AF: 0.00666 AC: 1013 AN: 152202 Hom.: 7 Cov.: 31 AF XY: 0.00646 AC XY: 481 AN XY: 74404

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0158

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00859 Hom.: 5

Bravo AF: 0.00670

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SLC12A5: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

Developmental and epileptic encephalopathy, 34 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

SLC12A5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2019

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	8.6
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.19
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: rs147042920; hg19: chr20-44665889;