chr20-46022977-A-AGGAG

Variant names:

• chr20-46022977-A-AGGAG
• rs1600581884
• ENST00000626701.1:c.257_258insGAGG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001134771.2(SLC12A5):​c.121+1092_121+1093insGAGG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC12A5 NM_001134771.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• 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: Illumina, PanelApp Australia, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 20-46022977-A-AGGAG is Benign according to our data. Variant chr20-46022977-A-AGGAG is described in ClinVar as Benign. ClinVar VariationId is 1686327.Status of the report is criteria_provided_single_submitter, 1 stars.

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+1092_121+1093insGAGG		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.257_258insGAGG	p.Gly87ArgfsTer98	frameshift	Exon 2 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.95_96insGAGG	p.Gly33GlyfsTer37	frameshift	Exon 2 of 3	ENSP00000487291.1	A0A0D9SGA5
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1092_121+1093insGAGG		intron	N/A	ENSP00000387694.1	Q9H2X9-1

Frequencies

GnomAD3 genomes AF: 0.00448 AC: 363 AN: 80976 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00701

Gnomad AMI AF: 0.00177

Gnomad AMR AF: 0.00182

Gnomad ASJ AF: 0.00248

Gnomad EAS AF: 0.00272

Gnomad SAS AF: 0.00346

Gnomad FIN AF: 0.00416

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.00178

GnomAD4 exome AF: 0.000129 AC: 22 AN: 170726 Hom.: 0 Cov.: 0 AF XY: 0.000160 AC XY: 14 AN XY: 87670

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

African (AFR) AF: 0.00163 AC: 9 AN: 5512

American (AMR) AF: 0.000489 AC: 2 AN: 4090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6030

East Asian (EAS) AF: 0.00 AC: 0 AN: 12766

South Asian (SAS) AF: 0.00 AC: 0 AN: 2002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 958

European-Non Finnish (NFE) AF: 0.0000704 AC: 8 AN: 113586

Other (OTH) AF: 0.000266 AC: 3 AN: 11268

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00451 AC: 365 AN: 80994 Hom.: 0 Cov.: 30 AF XY: 0.00439 AC XY: 170 AN XY: 38706

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

African (AFR) AF: 0.00705 AC: 146 AN: 20716

American (AMR) AF: 0.00182 AC: 16 AN: 8814

Ashkenazi Jewish (ASJ) AF: 0.00248 AC: 5 AN: 2016

East Asian (EAS) AF: 0.00273 AC: 5 AN: 1834

South Asian (SAS) AF: 0.00347 AC: 7 AN: 2016

European-Finnish (FIN) AF: 0.00416 AC: 23 AN: 5528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 146

European-Non Finnish (NFE) AF: 0.00416 AC: 159 AN: 38226

Other (OTH) AF: 0.00265 AC: 3 AN: 1132

⚠️ 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.

ClinVar

ClinVar submissions

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		0.0
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: rs1600581884; hg19: chr20-44651616;