chr20-46053031-C-G

Position:

chr20-46053031-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP2BP4_StrongBS1_Supporting

The NM_020708.5(SLC12A5):c.2452C>G(p.Pro818Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P818T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

SLC12A5
NM_020708.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.65

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. 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=0.047369003).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000302 (46/152178) while in subpopulation NFE AF= 0.000529 (36/68024). AF 95% confidence interval is 0.000392. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A5	NM_020708.5 linkuse as main transcript	c.2452C>G	p.Pro818Ala	missense_variant	19/26	ENST00000243964.7
SLC12A5	NM_001134771.2 linkuse as main transcript	c.2521C>G	p.Pro841Ala	missense_variant	19/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A5	ENST00000243964.7 linkuse as main transcript	c.2452C>G	p.Pro818Ala	missense_variant	19/26	1	NM_020708.5	A1	Q9H2X9-2

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000529

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000179

AC:

AN:

251452

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000510

AC:

745

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000466

AC XY:

339

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000613

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000302

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000290

Hom.:

Bravo

AF:

0.000344

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 34

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 29, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 27, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.2521C>G (p.P841A) alteration is located in exon 19 (coding exon 19) of the SLC12A5 gene. This alteration results from a C to G substitution at nucleotide position 2521, causing the proline (P) at amino acid position 841 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.48

DEOGEN2

Benign

0.060

T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

-0.55

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.18

N;N

REVEL

Benign

0.20

Sift

Benign

0.76

T;T

Sift4G

Benign

0.77

T;T

Polyphen

0.0

B;B

Vest4

0.17

MVP

0.18

MPC

0.93

ClinPred

0.011

GERP RS

4.5

Varity_R

0.17

gMVP

0.64

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over