20-46022943-GGGAGGAGGAGGAGGAGGAGGAGGA-GGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr20-46022943-GGGA-G
• rs34923327
• ENST00000626701.1:c.253_255delGGA

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+1088_121+1090delGGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 357,740 control chromosomes in the GnomAD database, including 493 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.044 (201 hom., cov: 0)
  • Exomes 𝑓: 0.042 (292 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-GGGA-G is Benign according to our data. Variant chr20-46022943-GGGA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3911458.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.187 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+1088_121+1090delGGA		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.253_255delGGA	p.Gly85del	conservative_inframe_deletion	Exon 2 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.91_93delGGA	p.Gly31del	conservative_inframe_deletion	Exon 2 of 3	ENSP00000487291.1	A0A0D9SGA5
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1088_121+1090delGGA		intron	N/A	ENSP00000387694.1	Q9H2X9-1

Frequencies

GnomAD3 genomes AF: 0.0439 AC: 5318 AN: 121154 Hom.: 202 Cov.: 0

Gnomad AFR AF: 0.0703

Gnomad AMI AF: 0.0169

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.0530

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00794

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.0437

GnomAD4 exome AF: 0.0419 AC: 9899 AN: 236530 Hom.: 292 AF XY: 0.0407 AC XY: 4935 AN XY: 121178

African (AFR) AF: 0.0648 AC: 422 AN: 6514

American (AMR) AF: 0.0338 AC: 240 AN: 7106

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 333 AN: 8696

East Asian (EAS) AF: 0.170 AC: 3780 AN: 22270

South Asian (SAS) AF: 0.0389 AC: 114 AN: 2930

European-Finnish (FIN) AF: 0.0175 AC: 347 AN: 19856

Middle Eastern (MID) AF: 0.0205 AC: 25 AN: 1218

European-Non Finnish (NFE) AF: 0.0259 AC: 3944 AN: 152376

Other (OTH) AF: 0.0446 AC: 694 AN: 15564

GnomAD4 genome AF: 0.0438 AC: 5315 AN: 121210 Hom.: 201 Cov.: 0 AF XY: 0.0454 AC XY: 2634 AN XY: 58004

African (AFR) AF: 0.0702 AC: 1964 AN: 27992

American (AMR) AF: 0.0390 AC: 485 AN: 12448

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 111 AN: 3086

East Asian (EAS) AF: 0.198 AC: 848 AN: 4276

South Asian (SAS) AF: 0.0526 AC: 185 AN: 3518

European-Finnish (FIN) AF: 0.0188 AC: 148 AN: 7854

Middle Eastern (MID) AF: 0.00427 AC: 1 AN: 234

European-Non Finnish (NFE) AF: 0.0250 AC: 1486 AN: 59324

Other (OTH) AF: 0.0433 AC: 74 AN: 1708

Alfa AF: 0.00649 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		=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;