20-46022943-GGGAGGAGGAGGAGGAGGAGGAGGA-GGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr20-46022943-G-GGGAGGAGGAGGA
• rs34923327
• ENST00000626701.1:c.244_255dupGGAGGAGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001134771.2(SLC12A5):​c.121+1079_121+1090dupGGAGGAGGAGGA 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (43 hom., cov: 0)
  • Exomes 𝑓: 0.043 (116 hom.)
• Consequence: SLC12A5 NM_001134771.2 intron
• Clinical Significance: 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 20-46022943-G-GGGAGGAGGAGGA is Benign according to our data. Variant chr20-46022943-G-GGGAGGAGGAGGA is described in ClinVar as Benign. ClinVar VariationId is 3911461.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 43 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+1079_121+1090dupGGAGGAGGAGGA		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.244_255dupGGAGGAGGAGGA	p.Gly82_Gly85dup	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.82_93dupGGAGGAGGAGGA	p.Gly28_Gly31dup	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487291.1	A0A0D9SGA5
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1079_121+1090dupGGAGGAGGAGGA		intron	N/A	ENSP00000387694.1	Q9H2X9-1

Frequencies

GnomAD3 genomes AF: 0.0268 AC: 3227 AN: 120510 Hom.: 43 Cov.: 0

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.0195

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0405

Gnomad EAS AF: 0.0140

Gnomad SAS AF: 0.0307

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0238

Gnomad NFE AF: 0.0360

Gnomad OTH AF: 0.0285

GnomAD4 exome AF: 0.0432 AC: 10437 AN: 241846 Hom.: 116 Cov.: 0 AF XY: 0.0437 AC XY: 5411 AN XY: 123932

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

African (AFR) AF: 0.0236 AC: 160 AN: 6774

American (AMR) AF: 0.0255 AC: 184 AN: 7216

Ashkenazi Jewish (ASJ) AF: 0.0548 AC: 486 AN: 8868

East Asian (EAS) AF: 0.0164 AC: 363 AN: 22196

South Asian (SAS) AF: 0.0450 AC: 133 AN: 2954

European-Finnish (FIN) AF: 0.0429 AC: 867 AN: 20214

Middle Eastern (MID) AF: 0.0315 AC: 40 AN: 1268

European-Non Finnish (NFE) AF: 0.0483 AC: 7562 AN: 156412

Other (OTH) AF: 0.0403 AC: 642 AN: 15944

⚠️ 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: 0.0268 AC: 3228 AN: 120570 Hom.: 43 Cov.: 0 AF XY: 0.0252 AC XY: 1452 AN XY: 57726

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

African (AFR) AF: 0.0122 AC: 342 AN: 27932

American (AMR) AF: 0.0165 AC: 205 AN: 12416

Ashkenazi Jewish (ASJ) AF: 0.0405 AC: 124 AN: 3062

East Asian (EAS) AF: 0.0141 AC: 60 AN: 4262

South Asian (SAS) AF: 0.0308 AC: 108 AN: 3504

European-Finnish (FIN) AF: 0.0258 AC: 201 AN: 7802

Middle Eastern (MID) AF: 0.0256 AC: 6 AN: 234

European-Non Finnish (NFE) AF: 0.0360 AC: 2118 AN: 58888

Other (OTH) AF: 0.0288 AC: 49 AN: 1700

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0138 Hom.: 174

ClinVar

ClinVar submissions as Germline

Significance: 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;