chr20-46022943-GGGAGGAGGAGGAGGAGGAGGAGGA-G

Variant names:

• chr20-46022943-GGGAGGAGGAGGAGGAGGAGGAGGA-G
• rs34923327
• ENST00000626701.1:c.232_255delGGAGGAGGAGGAGGAGGAGGAGGA

Variant summary

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

The NM_001134771.2(SLC12A5):​c.121+1067_121+1090delGGAGGAGGAGGAGGAGGAGGAGGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 366,100 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.000099 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (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 nfe. GnomAd4 allele frequency = 0.0000991 (12/121150) while in subpopulation NFE AF = 0.000185 (11/59340). AF 95% confidence interval is 0.000103. There are 0 homozygotes in GnomAd4. There are 4 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+1067_121+1090delGGAGGAGGAGGAGGAGGAGGAGGA		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.232_255delGGAGGAGGAGGAGGAGGAGGAGGA	p.Gly78_Gly85del	conservative_inframe_deletion	Exon 2 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.70_93delGGAGGAGGAGGAGGAGGAGGAGGA	p.Gly24_Gly31del	conservative_inframe_deletion	Exon 2 of 3	ENSP00000487291.1	A0A0D9SGA5
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1067_121+1090delGGAGGAGGAGGAGGAGGAGGAGGA		intron	N/A	ENSP00000387694.1	Q9H2X9-1

Frequencies

GnomAD3 genomes AF: 0.0000991 AC: 12 AN: 121150 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000804

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: 0.000185

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 31 AN: 244950 Hom.: 0 AF XY: 0.0000956 AC XY: 12 AN XY: 125462

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

American (AMR) AF: 0.000137 AC: 1 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: 0.000781 AC: 1 AN: 1280

European-Non Finnish (NFE) AF: 0.000139 AC: 22 AN: 158690

Other (OTH) AF: 0.000372 AC: 6 AN: 16146

GnomAD4 genome AF: 0.0000991 AC: 12 AN: 121150 Hom.: 0 Cov.: 0 AF XY: 0.0000691 AC XY: 4 AN XY: 57914

African (AFR) AF: 0.00 AC: 0 AN: 27906

American (AMR) AF: 0.0000804 AC: 1 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: 0.000185 AC: 11 AN: 59340

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

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		=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;