20-46022943-GGGAGGAGGAGGAGGAGGAGGAGGA-GGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr20-46022943-G-GGGAGGAGGAGGAGGAGGA
• rs34923327
• ENST00000626701.1:c.238_255dupGGAGGAGGAGGAGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001134771.2(SLC12A5):​c.121+1073_121+1090dupGGAGGAGGAGGAGGAGGA variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0042 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: SLC12A5 NM_001134771.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• 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.

• BS2: High Homozygotes in GnomAd4 at 12 AR,AD gene

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+1073_121+1090dupGGAGGAGGAGGAGGAGGA		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.238_255dupGGAGGAGGAGGAGGAGGA	p.Gly80_Gly85dup	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.76_93dupGGAGGAGGAGGAGGAGGA	p.Gly26_Gly31dup	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487291.1	A0A0D9SGA5
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1073_121+1090dupGGAGGAGGAGGAGGAGGA		intron	N/A	ENSP00000387694.1	Q9H2X9-1

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 511 AN: 121016 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00130

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000649

Gnomad EAS AF: 0.000467

Gnomad SAS AF: 0.000566

Gnomad FIN AF: 0.000127

Gnomad MID AF: 0.00397

Gnomad NFE AF: 0.000506

Gnomad OTH AF: 0.00413

GnomAD4 exome AF: 0.00158 AC: 387 AN: 244662 Hom.: 2 Cov.: 0 AF XY: 0.00151 AC XY: 189 AN XY: 125328

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0312 AC: 209 AN: 6696

American (AMR) AF: 0.00262 AC: 19 AN: 7260

Ashkenazi Jewish (ASJ) AF: 0.000554 AC: 5 AN: 9018

East Asian (EAS) AF: 0.000899 AC: 20 AN: 22248

South Asian (SAS) AF: 0.000671 AC: 2 AN: 2980

European-Finnish (FIN) AF: 0.0000977 AC: 2 AN: 20470

Middle Eastern (MID) AF: 0.000785 AC: 1 AN: 1274

European-Non Finnish (NFE) AF: 0.000492 AC: 78 AN: 158618

Other (OTH) AF: 0.00317 AC: 51 AN: 16098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00421 AC: 510 AN: 121072 Hom.: 12 Cov.: 0 AF XY: 0.00428 AC XY: 248 AN XY: 57934

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0157 AC: 439 AN: 27874

American (AMR) AF: 0.00209 AC: 26 AN: 12440

Ashkenazi Jewish (ASJ) AF: 0.000649 AC: 2 AN: 3084

East Asian (EAS) AF: 0.000468 AC: 2 AN: 4272

South Asian (SAS) AF: 0.000568 AC: 2 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: 0.000506 AC: 30 AN: 59314

Other (OTH) AF: 0.00410 AC: 7 AN: 1708

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 174

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	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;