20-46022943-GGGAGGAGGAGGAGGAGGAGGAGGA-GGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr20-46022943-G-GGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA
• rs34923327
• ENST00000626701.1:c.255_256insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant summary

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

The NM_001134771.2(SLC12A5):​c.121+1090_121+1091insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA 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 0.00017 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000165 (20/121146) while in subpopulation AFR AF = 0.000717 (20/27904). AF 95% confidence interval is 0.000474. There are 0 homozygotes in GnomAd4. There are 12 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+1090_121+1091insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA		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.255_256insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA	p.Gly85_Arg86insGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.93_94insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA	p.Gly31_Arg32insGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487291.1	A0A0D9SGA5
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1090_121+1091insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA		intron	N/A	ENSP00000387694.1	Q9H2X9-1

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 20 AN: 121146 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000717

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000408 AC: 1 AN: 244952 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125464

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

African (AFR) AF: 0.000147 AC: 1 AN: 6802

American (AMR) AF: 0.00 AC: 0 AN: 7280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9018

East Asian (EAS) AF: 0.00 AC: 0 AN: 22284

South Asian (SAS) AF: 0.00 AC: 0 AN: 2980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1280

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 158692

Other (OTH) AF: 0.00 AC: 0 AN: 16146

⚠️ 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: 0.000165 AC: 20 AN: 121146 Hom.: 0 Cov.: 0 AF XY: 0.000207 AC XY: 12 AN XY: 57912

African (AFR) AF: 0.000717 AC: 20 AN: 27904

American (AMR) AF: 0.00 AC: 0 AN: 12434

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4282

South Asian (SAS) AF: 0.00 AC: 0 AN: 3532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59338

Other (OTH) AF: 0.00 AC: 0 AN: 1694

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;