20-46022943-GGGAGGAGGAGGAGGAGGAGGAGGA-GGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr20-46022943-G-GGGAGGAGGA
• rs34923327
• ENST00000626701.1:c.247_255dupGGAGGAGGA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001134771.2(SLC12A5):​c.121+1082_121+1090dupGGAGGAGGA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (23 hom., cov: 0)
  • Exomes 𝑓: 0.0092 (8 hom.)
• Consequence: SLC12A5 NM_001134771.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 20-46022943-G-GGGAGGAGGA is Benign according to our data. Variant chr20-46022943-G-GGGAGGAGGA is described in ClinVar as Likely_benign. ClinVar VariationId is 3911462.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1300/121040) while in subpopulation AFR AF = 0.0255 (712/27914). AF 95% confidence interval is 0.024. There are 23 homozygotes in GnomAd4. There are 597 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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+1082_121+1090dupGGAGGAGGA		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.247_255dupGGAGGAGGA	p.Gly83_Gly85dup	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.85_93dupGGAGGAGGA	p.Gly29_Gly31dup	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487291.1	A0A0D9SGA5
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1082_121+1090dupGGAGGAGGA		intron	N/A	ENSP00000387694.1	Q9H2X9-1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1300 AN: 120982 Hom.: 23 Cov.: 0

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00781

Gnomad ASJ AF: 0.0114

Gnomad EAS AF: 0.00140

Gnomad SAS AF: 0.0127

Gnomad FIN AF: 0.00599

Gnomad MID AF: 0.00800

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.0112

GnomAD4 exome AF: 0.00916 AC: 2238 AN: 244296 Hom.: 8 Cov.: 0 AF XY: 0.00889 AC XY: 1112 AN XY: 125128

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

African (AFR) AF: 0.0394 AC: 267 AN: 6772

American (AMR) AF: 0.00826 AC: 60 AN: 7260

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 124 AN: 8978

East Asian (EAS) AF: 0.00476 AC: 106 AN: 22264

South Asian (SAS) AF: 0.0121 AC: 36 AN: 2970

European-Finnish (FIN) AF: 0.00720 AC: 147 AN: 20422

Middle Eastern (MID) AF: 0.0102 AC: 13 AN: 1276

European-Non Finnish (NFE) AF: 0.00817 AC: 1293 AN: 158270

Other (OTH) AF: 0.0119 AC: 192 AN: 16084

⚠️ 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: 0.0107 AC: 1300 AN: 121040 Hom.: 23 Cov.: 0 AF XY: 0.0103 AC XY: 597 AN XY: 57918

African (AFR) AF: 0.0255 AC: 712 AN: 27914

American (AMR) AF: 0.00764 AC: 95 AN: 12438

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 35 AN: 3082

East Asian (EAS) AF: 0.00141 AC: 6 AN: 4270

South Asian (SAS) AF: 0.0128 AC: 45 AN: 3520

European-Finnish (FIN) AF: 0.00599 AC: 47 AN: 7846

Middle Eastern (MID) AF: 0.00862 AC: 2 AN: 232

European-Non Finnish (NFE) AF: 0.00572 AC: 339 AN: 59264

Other (OTH) AF: 0.0112 AC: 19 AN: 1704

Alfa AF: 0.00324 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		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;