rs199934904

Positions:

• chr20-46056202-C-A
• chr20-46056202-C-G

Variant summary

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

The NM_020708.5(SLC12A5):​c.2840C>A​(p.Ala947Asp) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A947G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC12A5 NM_020708.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

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]

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 6.2616 (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=0.28970736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A5	NM_020708.5	c.2840C>A	p.Ala947Asp	missense_variant	22/26	ENST00000243964.7
SLC12A5	NM_001134771.2	c.2909C>A	p.Ala970Asp	missense_variant	22/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A5	ENST00000243964.7	c.2840C>A	p.Ala947Asp	missense_variant	22/26	1	NM_020708.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 34 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC12A5 protein function. ClinVar contains an entry for this variant (Variation ID: 1419227). This variant has not been reported in the literature in individuals affected with SLC12A5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 947 of the SLC12A5 protein (p.Ala947Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.50
Sift	Benign	0.31	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.026	B;B
Vest4		0.55
MutPred		0.29		Gain of helix (P = 0.0225);.;
MVP		0.51
MPC		0.25
ClinPred		0.64	D
GERP RS		4.8
Varity_R		0.30
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-44684841;