20-46022943-GGGAGGAGGAGGAGGAGGAGGAGGA-GGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr20-46022943-G-GGGAGGAGGAGGAGGA
• rs34923327
• ENST00000626701.1:c.241_255dupGGAGGAGGAGGAGGA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001134771.2(SLC12A5):​c.121+1076_121+1090dupGGAGGAGGAGGAGGA 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (7 hom., cov: 0)
  • Exomes 𝑓: 0.0087 (14 hom.)
• Consequence: SLC12A5 NM_001134771.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -12 ACMG points.

• BP6: Variant 20-46022943-G-GGGAGGAGGAGGAGGA is Benign according to our data. Variant chr20-46022943-G-GGGAGGAGGAGGAGGA is described in ClinVar as Likely_benign. ClinVar VariationId is 2652359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 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+1076_121+1090dupGGAGGAGGAGGAGGA		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.241_255dupGGAGGAGGAGGAGGA	p.Gly81_Gly85dup	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.79_93dupGGAGGAGGAGGAGGA	p.Gly27_Gly31dup	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487291.1	A0A0D9SGA5
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1076_121+1090dupGGAGGAGGAGGAGGA		intron	N/A	ENSP00000387694.1	Q9H2X9-1

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 822 AN: 120812 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.00629

Gnomad AMI AF: 0.00390

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00520

Gnomad EAS AF: 0.00304

Gnomad SAS AF: 0.00368

Gnomad FIN AF: 0.00127

Gnomad MID AF: 0.00794

Gnomad NFE AF: 0.00862

Gnomad OTH AF: 0.00653

GnomAD4 exome AF: 0.00872 AC: 2120 AN: 243176 Hom.: 14 Cov.: 0 AF XY: 0.00860 AC XY: 1071 AN XY: 124572

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

African (AFR) AF: 0.00769 AC: 52 AN: 6760

American (AMR) AF: 0.00843 AC: 61 AN: 7234

Ashkenazi Jewish (ASJ) AF: 0.00637 AC: 57 AN: 8954

East Asian (EAS) AF: 0.00148 AC: 33 AN: 22234

South Asian (SAS) AF: 0.00370 AC: 11 AN: 2970

European-Finnish (FIN) AF: 0.00377 AC: 77 AN: 20438

Middle Eastern (MID) AF: 0.0126 AC: 16 AN: 1268

European-Non Finnish (NFE) AF: 0.0105 AC: 1659 AN: 157290

Other (OTH) AF: 0.00961 AC: 154 AN: 16028

⚠️ 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: 0.00679 AC: 821 AN: 120870 Hom.: 7 Cov.: 0 AF XY: 0.00600 AC XY: 347 AN XY: 57844

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

African (AFR) AF: 0.00627 AC: 175 AN: 27904

American (AMR) AF: 0.00556 AC: 69 AN: 12414

Ashkenazi Jewish (ASJ) AF: 0.00520 AC: 16 AN: 3078

East Asian (EAS) AF: 0.00304 AC: 13 AN: 4270

South Asian (SAS) AF: 0.00398 AC: 14 AN: 3518

European-Finnish (FIN) AF: 0.00127 AC: 10 AN: 7852

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

European-Non Finnish (NFE) AF: 0.00862 AC: 510 AN: 59132

Other (OTH) AF: 0.00589 AC: 10 AN: 1698

⚠️ 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: 0.00 Hom.: 174

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	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;