20-46051869-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_020708.5(SLC12A5):c.2376T>C(p.Ile792Ile) 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
NM_020708.5 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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 34
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: 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, Ambry Genetics
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

SLC12A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

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 submission is: [Conflicting_classifications_of_pathogenicity].

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 the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5 link	c.2376T>C	p.Ile792Ile	splice_region_variant, synonymous_variant	Exon 18 of 26	ENST00000243964.7	NP_065759.1	Q9H2X9-2
SLC12A5	NM_001134771.2 link	c.2445T>C	p.Ile815Ile	splice_region_variant, synonymous_variant	Exon 18 of 26		NP_001128243.1	Q9H2X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7 link	c.2376T>C	p.Ile792Ile	splice_region_variant, synonymous_variant	Exon 18 of 26	1	NM_020708.5	ENSP00000243964.4		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

GnomAD2 exomes

AF:

0.000159

AC:

AN:

188656

AF XY:

0.000133

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 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

African (AFR)

AF:

0.00300

AC:

AN:

21686

American (AMR)

AF:

0.000599

AC:

AN:

26728

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16610

East Asian (EAS)

AF:

0.00

AC:

AN:

14662

South Asian (SAS)

AF:

0.00

AC:

AN:

72606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30982

Middle Eastern (MID)

AF:

0.000909

AC:

AN:

4400

European-Non Finnish (NFE)

AF:

0.0000706

AC:

AN:

863668

Other (OTH)

AF:

0.000483

AC:

AN:

41368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000633

AC:

AN:

115412

Hom.:

Cov.:

AF XY:

0.000815

AC XY:

AN XY:

52790

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

29728

American (AMR)

AF:

0.00132

AC:

AN:

8346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3226

East Asian (EAS)

AF:

0.00

AC:

AN:

3562

South Asian (SAS)

AF:

0.00

AC:

AN:

3470

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.0000165

AC:

AN:

60434

Other (OTH)

AF:

0.00188

AC:

AN:

1596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Feb 09, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 34

Uncertain:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC12A5: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.23

(source)

DANN

Benign

0.65

PhyloP100

-3.1

Mutation Taster

=36/64

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over