NM_020708.5:c.851T>G

Variant names:

• chr20-46040611-T-G
• rs1213597825
• NM_020708.5:c.851T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020708.5(SLC12A5):​c.851T>G​(p.Phe284Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC12A5 NM_020708.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• 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: 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

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.851T>G	p.Phe284Cys	missense	Exon 7 of 26	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.920T>G	p.Phe307Cys	missense	Exon 7 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.851T>G	p.Phe284Cys	missense	Exon 7 of 26	ENSP00000243964.4	Q9H2X9-2
	SLC12A5	ENST00000616202.4	TSL:1	c.612+3226T>G		intron	N/A	ENSP00000478369.1	M4PM71
	SLC12A5	ENST00000626937.2	TSL:1	c.509+3329T>G		intron	N/A	ENSP00000485953.1	M4PNC0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111900

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.025	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.80
MutPred		0.58		Gain of helix (P = 0.062)
MVP		0.87
MPC		2.5
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.65
gMVP		0.99
Mutation Taster		=10/90	disease causing

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: rs1213597825; hg19: chr20-44669250;