chr20-46051869-T-C

Position:

chr20-46051869-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS1

The ENST00000243964.7(SLC12A5):c.2376T>C(p.Ile792=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,208,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

SLC12A5
ENST00000243964.7 splice_region, synonymous

Scores

Splicing: ADA: 0.00006808

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -3.12

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 Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 20-46051869-T-C is Benign according to our data. Variant chr20-46051869-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475649.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BP7

Synonymous conserved (PhyloP=-3.12 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000633 (73/115412) while in subpopulation AFR AF= 0.00195 (58/29728). AF 95% confidence interval is 0.00155. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A5	NM_020708.5 linkuse as main transcript	c.2376T>C	p.Ile792=	splice_region_variant, synonymous_variant	18/26	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2 linkuse as main transcript	c.2445T>C	p.Ile815=	splice_region_variant, synonymous_variant	18/26		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7 linkuse as main transcript	c.2376T>C	p.Ile792=	splice_region_variant, synonymous_variant	18/26	1	NM_020708.5	ENSP00000243964	A1	Q9H2X9-2

Frequencies

GnomAD3 genomes

AF:

0.000615

AC:

AN:

115374

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00132

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:

0.0000165

Gnomad OTH

AF:

0.00189

GnomAD3 exomes

AF:

0.000159

AC:

AN:

188656

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

105018

show subpopulations

Gnomad AFR exome

AF:

0.000591

Gnomad AMR exome

AF:

0.000637

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000765

Gnomad OTH exome

AF:

0.000466

GnomAD4 exome

AF:

0.000152

AC:

166

AN:

1092710

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

541464

show subpopulations

Gnomad4 AFR exome

AF:

0.00300

Gnomad4 AMR exome

AF:

0.000599

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000706

Gnomad4 OTH exome

AF:

0.000483

GnomAD4 genome

AF:

0.000633

AC:

AN:

115412

Hom.:

Cov.:

AF XY:

0.000815

AC XY:

AN XY:

52790

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.00132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000165

Gnomad4 OTH

AF:

0.00188

Alfa

AF:

0.0000855

Hom.:

Bravo

AF:

0.000725

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

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

Feb 09, 2021

- -

Developmental and epileptic encephalopathy, 34

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

This sequence change affects codon 792 of the SLC12A5 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SLC12A5 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201525976, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with SLC12A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 475649). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

SLC12A5: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.23

DANN

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000068

dbscSNV1_RF

Benign

0.052

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