rs12481488

chr20-46048088-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020708.5(SLC12A5):c.2012+3T>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,608,780 control chromosomes in the GnomAD database, including 1,049 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (164 hom., cov: 31)
  • Exomes 𝑓: 0.027 (885 hom.)
• Consequence: SLC12A5 NM_020708.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00005421
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.946

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 20-46048088-T-A is Benign according to our data. Variant chr20-46048088-T-A is described in ClinVar as [Benign]. Clinvar id is 475644.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A5	NM_020708.5	c.2012+3T>A		splice_donor_region_variant, intron_variant		ENST00000243964.7
SLC12A5	NM_001134771.2	c.2081+3T>A		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A5	ENST00000243964.7	c.2012+3T>A		splice_donor_region_variant, intron_variant		1	NM_020708.5	A1

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4597 AN: 151894 Hom.: 162 Cov.: 31

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0364

GnomAD3 exomes AF: 0.0396 AC: 9514 AN: 240124 Hom.: 392 AF XY: 0.0363 AC XY: 4706 AN XY: 129662

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.0497

Gnomad EAS exome AF: 0.0341

Gnomad SAS exome AF: 0.0309

Gnomad FIN exome AF: 0.0224

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0378

GnomAD4 exome AF: 0.0272 AC: 39618 AN: 1456768 Hom.: 885 Cov.: 31 AF XY: 0.0270 AC XY: 19522 AN XY: 724060

Gnomad4 AFR exome AF: 0.0125

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.0517

Gnomad4 EAS exome AF: 0.0231

Gnomad4 SAS exome AF: 0.0299

Gnomad4 FIN exome AF: 0.0197

Gnomad4 NFE exome AF: 0.0233

Gnomad4 OTH exome AF: 0.0308

GnomAD4 genome AF: 0.0303 AC: 4606 AN: 152012 Hom.: 164 Cov.: 31 AF XY: 0.0320 AC XY: 2381 AN XY: 74328

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.0530

Gnomad4 EAS AF: 0.0252

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.0370

Alfa AF: 0.0256 Hom.: 29

Bravo AF: 0.0354

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 34 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.051
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.010		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: rs12481488; hg19: chr20-44676727; COSMIC: COSV54795084; COSMIC: COSV54795084;