rs12481488

Variant names:

• chr20-46048088-T-A
• rs12481488
• NM_020708.5:c.2012+3T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020708.5(SLC12A5):​c.2012+3T>A variant causes a splice 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.00005421
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.946
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 34

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• epilepsy of infancy with migrating focal seizures

  Inheritance: AR Classification: STRONG Submitted by: G2P
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, idiopathic generalized, susceptibility to, 14

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, PanelApp Australia, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 475644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020708.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	NM_020708.5	MANE Select	c.2012+3T>A		splice_region intron	N/A	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.2081+3T>A		splice_region intron	N/A	NP_001128243.1	Q9H2X9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	ENST00000243964.7	TSL:1 MANE Select	c.2012+3T>A		splice_region intron	N/A	ENSP00000243964.4	Q9H2X9-2
	SLC12A5	ENST00000616202.4	TSL:1	c.613-10393T>A		intron	N/A	ENSP00000478369.1	M4PM71
	SLC12A5	ENST00000626937.2	TSL:1	c.509+10806T>A		intron	N/A	ENSP00000485953.1	M4PNC0

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

GnomAD2 exomes AF: 0.0396 AC: 9514 AN: 240124 AF XY: 0.0363

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 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

African (AFR) AF: 0.0125 AC: 417 AN: 33426

American (AMR) AF: 0.128 AC: 5605 AN: 43954

Ashkenazi Jewish (ASJ) AF: 0.0517 AC: 1343 AN: 25962

East Asian (EAS) AF: 0.0231 AC: 915 AN: 39612

South Asian (SAS) AF: 0.0299 AC: 2553 AN: 85256

European-Finnish (FIN) AF: 0.0197 AC: 1046 AN: 53126

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5756

European-Non Finnish (NFE) AF: 0.0233 AC: 25798 AN: 1109512

Other (OTH) AF: 0.0308 AC: 1854 AN: 60164

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

African (AFR) AF: 0.0143 AC: 594 AN: 41454

American (AMR) AF: 0.111 AC: 1694 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3470

East Asian (EAS) AF: 0.0252 AC: 130 AN: 5160

South Asian (SAS) AF: 0.0261 AC: 125 AN: 4788

European-Finnish (FIN) AF: 0.0190 AC: 202 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0229 AC: 1559 AN: 67942

Other (OTH) AF: 0.0370 AC: 78 AN: 2110

Alfa AF: 0.0256 Hom.: 29

Bravo AF: 0.0354

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 34 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.051
DANN	Benign	0.70
PhyloP100		-0.95
Mutation Taster		=57/43	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12481488; hg19: chr20-44676727; COSMIC: COSV54795084; COSMIC: COSV54795084;