20-46049694-C-T

Variant names:

• chr20-46049694-C-T
• rs747468488
• NM_020708.5:c.2085C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS1

The NM_001134771.2(SLC12A5):​c.2154C>T​(p.Thr718Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 1,454,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SLC12A5 NM_001134771.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.294
• Publications: 1 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: 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, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 20-46049694-C-T is Benign according to our data. Variant chr20-46049694-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 542332.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.294 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000894 (13/1454454) while in subpopulation SAS AF = 0.0000949 (8/84302). AF 95% confidence interval is 0.0000467. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	NM_020708.5	MANE Select	c.2085C>T	p.Thr695Thr	synonymous	Exon 17 of 26	NP_065759.1
	SLC12A5	NM_001134771.2		c.2154C>T	p.Thr718Thr	synonymous	Exon 17 of 26	NP_001128243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	ENST00000243964.7	TSL:1 MANE Select	c.2085C>T	p.Thr695Thr	synonymous	Exon 17 of 26	ENSP00000243964.4
	SLC12A5	ENST00000616202.4	TSL:1	c.613-8787C>T		intron	N/A	ENSP00000478369.1
	SLC12A5	ENST00000626937.2	TSL:1	c.510-9905C>T		intron	N/A	ENSP00000485953.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000127 AC: 3 AN: 235724 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000937

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000894 AC: 13 AN: 1454454 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10 AN XY: 722554

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.0000460 AC: 2 AN: 43484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.0000949 AC: 8 AN: 84302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109010

Other (OTH) AF: 0.0000332 AC: 2 AN: 60176

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 34 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.2
DANN	Benign	0.67
PhyloP100		-0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs747468488; hg19: chr20-44678333;