NM_020708.5:c.280-106A>G

Variant names:

• chr20-46035671-A-G
• rs3848723
• NM_020708.5:c.280-106A>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.280-106A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,516,658 control chromosomes in the GnomAD database, including 1,057 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 0.029 (173 hom., cov: 32)
  • Exomes 𝑓: 0.027 (884 hom.)
• Consequence: SLC12A5 NM_020708.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0420
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.112 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	NM_020708.5	MANE Select	c.280-106A>G		intron	N/A	NP_065759.1
	SLC12A5	NM_001134771.2		c.349-106A>G		intron	N/A	NP_001128243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	ENST00000243964.7	TSL:1 MANE Select	c.280-106A>G		intron	N/A	ENSP00000243964.4
	SLC12A5	ENST00000616202.4	TSL:1	c.280-106A>G		intron	N/A	ENSP00000478369.1
	SLC12A5	ENST00000626937.2	TSL:1	c.280-106A>G		intron	N/A	ENSP00000485953.1

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4457 AN: 151970 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.00805

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.0388

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0335

GnomAD4 exome AF: 0.0273 AC: 37295 AN: 1364570 Hom.: 884 Cov.: 26 AF XY: 0.0276 AC XY: 18476 AN XY: 669826

African (AFR) AF: 0.00513 AC: 161 AN: 31388

American (AMR) AF: 0.148 AC: 5127 AN: 34620

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 1138 AN: 21588

East Asian (EAS) AF: 0.0360 AC: 1372 AN: 38094

South Asian (SAS) AF: 0.0420 AC: 3080 AN: 73398

European-Finnish (FIN) AF: 0.0184 AC: 847 AN: 46058

Middle Eastern (MID) AF: 0.0168 AC: 74 AN: 4406

European-Non Finnish (NFE) AF: 0.0225 AC: 23778 AN: 1058470

Other (OTH) AF: 0.0304 AC: 1718 AN: 56548

GnomAD4 genome AF: 0.0293 AC: 4461 AN: 152088 Hom.: 173 Cov.: 32 AF XY: 0.0312 AC XY: 2323 AN XY: 74366

African (AFR) AF: 0.00803 AC: 333 AN: 41482

American (AMR) AF: 0.117 AC: 1787 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0539 AC: 187 AN: 3470

East Asian (EAS) AF: 0.0284 AC: 147 AN: 5174

South Asian (SAS) AF: 0.0388 AC: 187 AN: 4818

European-Finnish (FIN) AF: 0.0182 AC: 192 AN: 10578

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

European-Non Finnish (NFE) AF: 0.0223 AC: 1519 AN: 67966

Other (OTH) AF: 0.0336 AC: 71 AN: 2110

Alfa AF: 0.0231 Hom.: 11

Bravo AF: 0.0348

Asia WGS AF: 0.0320 AC: 111 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.6
DANN	Benign	0.52
PhyloP100		-0.042
Mutation Taster		=100/0	polymorphism (auto)

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: rs3848723; hg19: chr20-44664310;