ENST00000626701.1:c.255_256insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr20-46022943-G-GGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA
• rs34923327
• ENST00000626701.1:c.255_256insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS1

The ENST00000626701.1(SLC12A5):​c.255_256insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA​(p.Gly85_Arg86insGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGly) variant causes a conservative inframe insertion 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SLC12A5 ENST00000626701.1 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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 -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000626701.1
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000124 (15/121146) while in subpopulation AFR AF = 0.000251 (7/27906). AF 95% confidence interval is 0.000118. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000626701.1. 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+1090_121+1091insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA		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.255_256insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA	p.Gly85_Arg86insGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.93_94insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA	p.Gly31_Arg32insGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 2 of 3	ENSP00000487291.1	A0A0D9SGA5
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1090_121+1091insGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA		intron	N/A	ENSP00000387694.1	Q9H2X9-1

Frequencies

GnomAD3 genomes AF: 0.000124 AC: 15 AN: 121146 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000324

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000408 AC: 1 AN: 244950 Hom.: 0 Cov.: 0 AF XY: 0.00000797 AC XY: 1 AN XY: 125464

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

African (AFR) AF: 0.000147 AC: 1 AN: 6800

American (AMR) AF: 0.00 AC: 0 AN: 7280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9018

East Asian (EAS) AF: 0.00 AC: 0 AN: 22284

South Asian (SAS) AF: 0.00 AC: 0 AN: 2980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1280

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 158692

Other (OTH) AF: 0.00 AC: 0 AN: 16146

⚠️ 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: 0.000124 AC: 15 AN: 121146 Hom.: 0 Cov.: 0 AF XY: 0.000121 AC XY: 7 AN XY: 57914

African (AFR) AF: 0.000251 AC: 7 AN: 27906

American (AMR) AF: 0.00 AC: 0 AN: 12432

Ashkenazi Jewish (ASJ) AF: 0.000324 AC: 1 AN: 3084

East Asian (EAS) AF: 0.00 AC: 0 AN: 4282

South Asian (SAS) AF: 0.00 AC: 0 AN: 3532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.000118 AC: 7 AN: 59338

Other (OTH) AF: 0.00 AC: 0 AN: 1694

ClinVar

Not reported in ClinVar

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;