rs147042920

Variant names:

• chr20-46037250-T-C
• rs147042920
• NM_020708.5:c.482-5T>C

Variant summary

Our verdict is Benign. The variant received -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, 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (7 hom., cov: 31)
  • Exomes 𝑓: 0.010 (105 hom.)
• Consequence: SLC12A5 NM_020708.5 splice_region, intron
• Scores: Splicing: ADA: 0.002407
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.827
• Publications: 1 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 -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 Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

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.482-5T>C		splice_region intron	N/A	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.551-5T>C		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.482-5T>C		splice_region intron	N/A	ENSP00000243964.4	Q9H2X9-2
	SLC12A5	ENST00000616202.4	TSL:1	c.482-5T>C		splice_region intron	N/A	ENSP00000478369.1	M4PM71
	SLC12A5	ENST00000626937.2	TSL:1	c.482-5T>C		splice_region intron	N/A	ENSP00000485953.1	M4PNC0

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

GnomAD2 exomes AF: 0.00697 AC: 1656 AN: 237704 AF XY: 0.00755

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 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

African (AFR) AF: 0.00152 AC: 50 AN: 32890

American (AMR) AF: 0.00398 AC: 170 AN: 42752

Ashkenazi Jewish (ASJ) AF: 0.00659 AC: 164 AN: 24880

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39446

South Asian (SAS) AF: 0.0123 AC: 1028 AN: 83748

European-Finnish (FIN) AF: 0.00326 AC: 172 AN: 52818

Middle Eastern (MID) AF: 0.0120 AC: 68 AN: 5644

European-Non Finnish (NFE) AF: 0.0114 AC: 12548 AN: 1102142

Other (OTH) AF: 0.0100 AC: 598 AN: 59562

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

African (AFR) AF: 0.00176 AC: 73 AN: 41532

American (AMR) AF: 0.00543 AC: 83 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4816

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0108 AC: 734 AN: 68012

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00859 Hom.: 6

Bravo AF: 0.00670

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy, 34 (1)
-	-	1	SLC12A5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.6
DANN	Benign	0.87
PhyloP100		0.83
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs147042920; hg19: chr20-44665889;