rs16991026

Variant names:

• chr20-46051200-A-G
• rs16991026
• NM_020708.5:c.2182-475A>G

Variant summary

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

The NM_020708.5(SLC12A5):​c.2182-475A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0273 in 152,308 control chromosomes in the GnomAD database, including 150 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 0.027 (150 hom., cov: 32)
• Consequence: SLC12A5 NM_020708.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0750
• Publications: 5 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5	c.2182-475A>G		intron_variant	Intron 17 of 25	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2	c.2251-475A>G		intron_variant	Intron 17 of 25		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7	c.2182-475A>G		intron_variant	Intron 17 of 25	1	NM_020708.5	ENSP00000243964.4

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4157 AN: 152190 Hom.: 148 Cov.: 32

Gnomad AFR AF: 0.00738

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0330

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

GnomAD4 genome AF: 0.0273 AC: 4163 AN: 152308 Hom.: 150 Cov.: 32 AF XY: 0.0289 AC XY: 2152 AN XY: 74472

African (AFR) AF: 0.00736 AC: 306 AN: 41576

American (AMR) AF: 0.108 AC: 1645 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 180 AN: 3470

East Asian (EAS) AF: 0.00560 AC: 29 AN: 5178

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4820

European-Finnish (FIN) AF: 0.0193 AC: 205 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0230 AC: 1563 AN: 68016

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0284 Hom.: 24

Bravo AF: 0.0315

Asia WGS AF: 0.0200 AC: 68 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.44
DANN	Benign	0.44
PhyloP100		0.075
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs16991026; hg19: chr20-44679839;