20-46022943-GGGAGGAGGAGGAGGAGGAGGAGGA-GGGAGGAGGAGGAGGAGGA

Variant names:

• chr20-46022943-GGGAGGA-G
• rs34923327
• ENST00000626701.1:c.250_255delGGAGGA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001134771.2(SLC12A5):​c.121+1085_121+1090delGGAGGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0686 in 365,836 control chromosomes in the GnomAD database, including 1,624 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.065 (601 hom., cov: 0)
  • Exomes 𝑓: 0.071 (1023 hom.)
• Consequence: SLC12A5 NM_001134771.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.28
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 20-46022943-GGGAGGA-G is Benign according to our data. Variant chr20-46022943-GGGAGGA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3911457.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

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+1085_121+1090delGGAGGA		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.250_255delGGAGGA	p.Gly84_Gly85del	conservative_inframe_deletion	Exon 2 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.88_93delGGAGGA	p.Gly30_Gly31del	conservative_inframe_deletion	Exon 2 of 3	ENSP00000487291.1	A0A0D9SGA5
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1085_121+1090delGGAGGA		intron	N/A	ENSP00000387694.1	Q9H2X9-1

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 7810 AN: 121146 Hom.: 594 Cov.: 0

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.0104

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.0470

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.0593

Gnomad MID AF: 0.0357

Gnomad NFE AF: 0.0401

Gnomad OTH AF: 0.0679

GnomAD4 exome AF: 0.0705 AC: 17254 AN: 244632 Hom.: 1023 AF XY: 0.0694 AC XY: 8697 AN XY: 125310

African (AFR) AF: 0.0174 AC: 118 AN: 6792

American (AMR) AF: 0.233 AC: 1693 AN: 7266

Ashkenazi Jewish (ASJ) AF: 0.0446 AC: 402 AN: 9016

East Asian (EAS) AF: 0.277 AC: 6128 AN: 22112

South Asian (SAS) AF: 0.145 AC: 432 AN: 2972

European-Finnish (FIN) AF: 0.0507 AC: 1037 AN: 20458

Middle Eastern (MID) AF: 0.0547 AC: 70 AN: 1280

European-Non Finnish (NFE) AF: 0.0399 AC: 6331 AN: 158602

Other (OTH) AF: 0.0646 AC: 1043 AN: 16134

GnomAD4 genome AF: 0.0646 AC: 7825 AN: 121204 Hom.: 601 Cov.: 0 AF XY: 0.0691 AC XY: 4008 AN XY: 58006

African (AFR) AF: 0.0218 AC: 609 AN: 27982

American (AMR) AF: 0.197 AC: 2449 AN: 12462

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 145 AN: 3084

East Asian (EAS) AF: 0.248 AC: 1060 AN: 4272

South Asian (SAS) AF: 0.164 AC: 577 AN: 3516

European-Finnish (FIN) AF: 0.0593 AC: 466 AN: 7860

Middle Eastern (MID) AF: 0.0342 AC: 8 AN: 234

European-Non Finnish (NFE) AF: 0.0401 AC: 2381 AN: 59316

Other (OTH) AF: 0.0714 AC: 122 AN: 1708

Alfa AF: 0.0166 Hom.: 174

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
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;