20-46021770-G-A

Position:

• chr20-46021770-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001134771.2(SLC12A5):​c.5G>A​(p.Ser2Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A5 NM_001134771.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.67

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-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC12A5. . Gene score misZ 4.7022 (greater than the threshold 3.09). Trascript score misZ 5.953 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 34, malignant migrating partial seizures of infancy, developmental and epileptic encephalopathy, epilepsy, idiopathic generalized, susceptibility to, 14.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3171978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A5	NM_001134771.2	c.5G>A	p.Ser2Asn	missense_variant	1/26		NP_001128243.1
SLC12A5-AS1	NR_147699.1	n.304C>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000454036.6	c.5G>A	p.Ser2Asn	missense_variant	1/26	5		ENSP00000387694.1
SLC12A5	ENST00000626701.1	c.5G>A	p.Ser2Asn	missense_variant	1/3	3		ENSP00000487372.1
SLC12A5	ENST00000628272.1	c.5G>A	p.Ser2Asn	missense_variant	1/2	3		ENSP00000486382.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, idiopathic generalized, susceptibility to, 14;C4225257:Developmental and epileptic encephalopathy, 34 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 26, 2020

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.028
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.33	N;.;.
REVEL	Benign	0.28
Sift	Benign	0.18	T;.;.
Sift4G	Uncertain	0.034	D;D;T
Polyphen		0.29	B;.;.
Vest4		0.16
MutPred		0.20		Loss of phosphorylation at S2 (P = 0.0049);Loss of phosphorylation at S2 (P = 0.0049);Loss of phosphorylation at S2 (P = 0.0049);
MVP		0.32
MPC		0.90
ClinPred		0.61	D
GERP RS		4.6
Varity_R		0.19
gMVP		0.30

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs868778058; hg19: chr20-44650409; COSMIC: COSV69557058; COSMIC: COSV69557058;