chr20-46045891-G-A

Variant names:

• chr20-46045891-G-A
• rs863225305
• NM_020708.5:c.1583G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_020708.5(SLC12A5):​c.1583G>A​(p.Gly528Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A5 NM_020708.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 8.08
• Publications: 12 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: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849
• PP5: Variant 20-46045891-G-A is Pathogenic according to our data. Variant chr20-46045891-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 217905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1583G>A	p.Gly528Asp	missense	Exon 13 of 26	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.1652G>A	p.Gly551Asp	missense	Exon 13 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.1583G>A	p.Gly528Asp	missense	Exon 13 of 26	ENSP00000243964.4	Q9H2X9-2
	SLC12A5	ENST00000616202.4	TSL:1	c.612+8506G>A		intron	N/A	ENSP00000478369.1	M4PM71
	SLC12A5	ENST00000626937.2	TSL:1	c.509+8609G>A		intron	N/A	ENSP00000485953.1	M4PNC0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Developmental and epileptic encephalopathy, 34 (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		8.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.88
Sift	Benign	0.12	T
Sift4G	Benign	0.45	T
Polyphen		0.93	P
Vest4		0.76
MutPred		0.57		Gain of sheet (P = 0.0827)
MVP		0.92
MPC		2.4
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.83
gMVP		0.97
Mutation Taster		=21/79	disease causing (ClinVar)

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: rs863225305; hg19: chr20-44674530;