20-46024468-C-G

Variant names:

• chr20-46024468-C-G
• rs6094238
• NM_001134771.2:c.121+2582C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134771.2(SLC12A5):​c.121+2582C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 152,050 control chromosomes in the GnomAD database, including 8,278 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (8278 hom., cov: 32)
• Consequence: SLC12A5 NM_001134771.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.903
• Publications: 9 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: 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, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134771.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	NM_001134771.2		c.121+2582C>G		intron	N/A	NP_001128243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	ENST00000454036.6	TSL:5	c.121+2582C>G		intron	N/A	ENSP00000387694.1
	SLC12A5	ENST00000428198.1	TSL:3	n.111+2582C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47846 AN: 151932 Hom.: 8270 Cov.: 32

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.277

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.315 AC: 47887 AN: 152050 Hom.: 8278 Cov.: 32 AF XY: 0.316 AC XY: 23492 AN XY: 74332

African (AFR) AF: 0.470 AC: 19470 AN: 41418

American (AMR) AF: 0.285 AC: 4362 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 784 AN: 3470

East Asian (EAS) AF: 0.372 AC: 1926 AN: 5184

South Asian (SAS) AF: 0.405 AC: 1956 AN: 4824

European-Finnish (FIN) AF: 0.226 AC: 2389 AN: 10582

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16090 AN: 67976

Other (OTH) AF: 0.279 AC: 587 AN: 2106

Alfa AF: 0.275 Hom.: 792

Bravo AF: 0.324

Asia WGS AF: 0.365 AC: 1267 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.64
DANN	Benign	0.72
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6094238; hg19: chr20-44653107;