20-46022943-GGGAGGAGGAGGAGGAGGAGGAGGA-GGGAGGAGGAGGAGGA

Variant names:

• chr20-46022943-GGGAGGAGGA-G
• rs34923327
• ENST00000626701.1:c.247_255delGGAGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001134771.2(SLC12A5):​c.121+1082_121+1090delGGAGGAGGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 365,690 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: SLC12A5 NM_001134771.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.95
• Publications: 0 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Illumina
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0015 (182/121202) while in subpopulation AFR AF = 0.00565 (158/27988). AF 95% confidence interval is 0.00493. There are 0 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	NM_001134771.2		c.121+1082_121+1090delGGAGGAGGA		intron	N/A	NP_001128243.1	Q9H2X9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	ENST00000626701.1	TSL:3	c.247_255delGGAGGAGGA	p.Gly83_Gly85del	conservative_inframe_deletion	Exon 2 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.85_93delGGAGGAGGA	p.Gly29_Gly31del	conservative_inframe_deletion	Exon 2 of 3	ENSP00000487291.1	A0A0D9SGA5
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1082_121+1090delGGAGGAGGA		intron	N/A	ENSP00000387694.1	Q9H2X9-1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 181 AN: 121146 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00563

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000885

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000234

Gnomad SAS AF: 0.000283

Gnomad FIN AF: 0.000127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000135

Gnomad OTH AF: 0.00118

GnomAD4 exome AF: 0.000335 AC: 82 AN: 244488 Hom.: 0 AF XY: 0.000311 AC XY: 39 AN XY: 125228

African (AFR) AF: 0.00559 AC: 38 AN: 6800

American (AMR) AF: 0.000972 AC: 7 AN: 7198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9014

East Asian (EAS) AF: 0.000318 AC: 7 AN: 21994

South Asian (SAS) AF: 0.00 AC: 0 AN: 2974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1278

European-Non Finnish (NFE) AF: 0.000145 AC: 23 AN: 158648

Other (OTH) AF: 0.000434 AC: 7 AN: 16128

GnomAD4 genome AF: 0.00150 AC: 182 AN: 121202 Hom.: 0 Cov.: 0 AF XY: 0.00143 AC XY: 83 AN XY: 57992

African (AFR) AF: 0.00565 AC: 158 AN: 27988

American (AMR) AF: 0.000884 AC: 11 AN: 12444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3084

East Asian (EAS) AF: 0.000234 AC: 1 AN: 4272

South Asian (SAS) AF: 0.000284 AC: 1 AN: 3520

European-Finnish (FIN) AF: 0.000127 AC: 1 AN: 7856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.000135 AC: 8 AN: 59326

Other (OTH) AF: 0.00117 AC: 2 AN: 1708

Alfa AF: 0.00 Hom.: 174

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs34923327; hg19: chr20-44651582;