20-46029350-A-G

Variant names:

• chr20-46029350-A-G
• rs900869630
• NM_020708.5:c.6A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_020708.5(SLC12A5):​c.6A>G​(p.Leu2Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000084 in 1,548,476 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: SLC12A5 NM_020708.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.756
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 20-46029350-A-G is Benign according to our data. Variant chr20-46029350-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2161954.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.756 with no splicing effect.

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.6A>G	p.Leu2Leu	synonymous	Exon 1 of 26	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.122-5598A>G		intron	N/A	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.6A>G	p.Leu2Leu	synonymous	Exon 1 of 26	ENSP00000243964.4	Q9H2X9-2
	SLC12A5	ENST00000616202.4	TSL:1	c.6A>G	p.Leu2Leu	synonymous	Exon 1 of 7	ENSP00000478369.1	M4PM71
	SLC12A5	ENST00000626937.2	TSL:1	c.6A>G	p.Leu2Leu	synonymous	Exon 1 of 7	ENSP00000485953.1	M4PNC0

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000137 AC: 2 AN: 146444 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000372

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000859 AC: 12 AN: 1396314 Hom.: 0 Cov.: 32 AF XY: 0.00000726 AC XY: 5 AN XY: 688714

African (AFR) AF: 0.00 AC: 0 AN: 31434

American (AMR) AF: 0.00 AC: 0 AN: 35508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25078

East Asian (EAS) AF: 0.00 AC: 0 AN: 35460

South Asian (SAS) AF: 0.00 AC: 0 AN: 79076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1078132

Other (OTH) AF: 0.00 AC: 0 AN: 57898

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	-0.51
CADD	Benign	4.3
DANN	Benign	0.63
PhyloP100		-0.76
PromoterAI		0.053	Neutral

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: rs900869630; hg19: chr20-44657989;