20-46051785-G-T

Variant names:

• chr20-46051785-G-T
• rs79522550
• NM_020708.5:c.2292G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020708.5(SLC12A5):​c.2292G>T​(p.Gly764Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,608,856 control chromosomes in the GnomAD database, including 182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G764G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 31)
  • Exomes 𝑓: 0.013 (167 hom.)
• Consequence: SLC12A5 NM_020708.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.280
• Publications: 3 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 20-46051785-G-T is Benign according to our data. Variant chr20-46051785-G-T is described in ClinVar as Benign. ClinVar VariationId is 475647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0108 (1649/152294) while in subpopulation NFE AF = 0.0148 (1006/68022). AF 95% confidence interval is 0.014. There are 15 homozygotes in GnomAd4. There are 838 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020708.5. 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_020708.5	MANE Select	c.2292G>T	p.Gly764Gly	synonymous	Exon 18 of 26	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.2361G>T	p.Gly787Gly	synonymous	Exon 18 of 26	NP_001128243.1	Q9H2X9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	ENST00000243964.7	TSL:1 MANE Select	c.2292G>T	p.Gly764Gly	synonymous	Exon 18 of 26	ENSP00000243964.4	Q9H2X9-2
	SLC12A5	ENST00000616202.4	TSL:1	c.613-6696G>T		intron	N/A	ENSP00000478369.1	M4PM71
	SLC12A5	ENST00000626937.2	TSL:1	c.510-7814G>T		intron	N/A	ENSP00000485953.1	M4PNC0

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1650 AN: 152176 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0118 AC: 2875 AN: 244606 AF XY: 0.0119

Gnomad AFR exome AF: 0.00188

Gnomad AMR exome AF: 0.00616

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0271

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0132 AC: 19224 AN: 1456562 Hom.: 167 Cov.: 34 AF XY: 0.0129 AC XY: 9354 AN XY: 724628

African (AFR) AF: 0.00202 AC: 67 AN: 33190

American (AMR) AF: 0.00707 AC: 310 AN: 43846

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 396 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39136

South Asian (SAS) AF: 0.00578 AC: 494 AN: 85472

European-Finnish (FIN) AF: 0.0251 AC: 1337 AN: 53214

Middle Eastern (MID) AF: 0.0188 AC: 108 AN: 5752

European-Non Finnish (NFE) AF: 0.0142 AC: 15724 AN: 1109820

Other (OTH) AF: 0.0131 AC: 788 AN: 60186

GnomAD4 genome AF: 0.0108 AC: 1649 AN: 152294 Hom.: 15 Cov.: 31 AF XY: 0.0113 AC XY: 838 AN XY: 74476

African (AFR) AF: 0.00238 AC: 99 AN: 41558

American (AMR) AF: 0.00784 AC: 120 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4824

European-Finnish (FIN) AF: 0.0274 AC: 291 AN: 10614

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0148 AC: 1006 AN: 68022

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0124 Hom.: 13

Bravo AF: 0.00858

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 34 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.8
DANN	Benign	0.69
PhyloP100		-0.28
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs79522550; hg19: chr20-44680424;