Genetic Variant SLC12A5:c.2911-26C>T (chr20-46056339-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_020708.5(SLC12A5):c.2911-26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0853 in 1,608,382 control chromosomes in the GnomAD database, including 9,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.098 ( 1050 hom., cov: 33)

Exomes 𝑓: 0.084 ( 8156 hom. )

Consequence

SLC12A5
NM_020708.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.441

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 20-46056339-C-T is Benign according to our data. Variant chr20-46056339-C-T is described in ClinVar as [Benign]. Clinvar id is 3255279.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5 link	c.2911-26C>T		intron_variant	Intron 22 of 25	ENST00000243964.7	NP_065759.1	Q9H2X9-2
SLC12A5	NM_001134771.2 link	c.2980-26C>T		intron_variant	Intron 22 of 25		NP_001128243.1	Q9H2X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7 link	c.2911-26C>T		intron_variant	Intron 22 of 25	1	NM_020708.5	ENSP00000243964.4		Q9H2X9-2

Frequencies

GnomAD3 genomes

AF:

0.0980

AC:

14901

AN:

152108

Hom.:

1040

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.0659

Gnomad AMR

AF:

0.200

Gnomad ASJ

AF:

0.0340

Gnomad EAS

AF:

0.235

Gnomad SAS

AF:

0.148

Gnomad FIN

AF:

0.0485

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0610

Gnomad OTH

AF:

0.0992

GnomAD3 exomes

AF:

0.128

AC:

31490

AN:

246302

Hom.:

3657

AF XY:

0.118

AC XY:

15688

AN XY:

132976

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.360

Gnomad ASJ exome

AF:

0.0337

Gnomad EAS exome

AF:

0.223

Gnomad SAS exome

AF:

0.148

Gnomad FIN exome

AF:

0.0488

Gnomad NFE exome

AF:

0.0616

Gnomad OTH exome

AF:

0.0961

GnomAD4 exome

AF:

0.0840

AC:

122265

AN:

1456156

Hom.:

8156

Cov.:

AF XY:

0.0844

AC XY:

61090

AN XY:

723756

show subpopulations

Gnomad4 AFR exome

AF:

0.119

Gnomad4 AMR exome

AF:

0.342

Gnomad4 ASJ exome

AF:

0.0353

Gnomad4 EAS exome

AF:

0.256

Gnomad4 SAS exome

AF:

0.147

Gnomad4 FIN exome

AF:

0.0521

Gnomad4 NFE exome

AF:

0.0644

Gnomad4 OTH exome

AF:

0.0838

GnomAD4 genome

AF:

0.0981

AC:

14927

AN:

152226

Hom.:

1050

Cov.:

AF XY:

0.100

AC XY:

7465

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.117

Gnomad4 AMR

AF:

0.200

Gnomad4 ASJ

AF:

0.0340

Gnomad4 EAS

AF:

0.235

Gnomad4 SAS

AF:

0.147

Gnomad4 FIN

AF:

0.0485

Gnomad4 NFE

AF:

0.0611

Gnomad4 OTH

AF:

0.103

Alfa

AF:

0.0776

Hom.:

897

Bravo

AF:

0.115

Asia WGS

AF:

0.248

AC:

863

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 39. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.8

DANN

Benign

0.53

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