Genetic Variant NM_001365088.1:c.1825-13C>T (chr15-34245416-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001365088.1(SLC12A6):c.1825-13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,441,302 control chromosomes in the GnomAD database, including 10,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 894 hom., cov: 32)

Exomes 𝑓: 0.12 ( 9208 hom. )

Consequence

SLC12A6
NM_001365088.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.228

Variant links:

Genes affected

SLC12A6 (HGNC:10914): (solute carrier family 12 member 6) This gene is a member of the K-Cl cotransporter (KCC) family. K-Cl cotransporters are integral membrane proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The proteins encoded by this gene are activated by cell swelling induced by hypotonic conditions. Alternate splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are associated with agenesis of the corpus callosum with peripheral neuropathy. [provided by RefSeq, Jul 2008]

SLC12A6 links:

LOC124903461 (HGNC:):

LOC124903461 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 15-34245416-G-A is Benign according to our data. Variant chr15-34245416-G-A is described in ClinVar as [Benign]. Clinvar id is 159889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-34245416-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A6	NM_001365088.1 link	c.1825-13C>T		intron_variant	Intron 14 of 25	ENST00000354181.8	NP_001352017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A6	ENST00000354181.8 link	c.1825-13C>T		intron_variant	Intron 14 of 25	1	NM_001365088.1	ENSP00000346112.3		Q9UHW9-1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15571

AN:

152086

Hom.:

895

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0784

Gnomad AMI

AF:

0.180

Gnomad AMR

AF:

0.0748

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.0214

Gnomad SAS

AF:

0.153

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.0837

GnomAD3 exomes

AF:

0.106

AC:

26682

AN:

251330

Hom.:

1631

AF XY:

0.110

AC XY:

14910

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0769

Gnomad AMR exome

AF:

0.0761

Gnomad ASJ exome

AF:

0.142

Gnomad EAS exome

AF:

0.0225

Gnomad SAS exome

AF:

0.149

Gnomad FIN exome

AF:

0.103

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.110

GnomAD4 exome

AF:

0.117

AC:

150571

AN:

1289098

Hom.:

9208

Cov.:

AF XY:

0.118

AC XY:

76718

AN XY:

650570

show subpopulations

Gnomad4 AFR exome

AF:

0.0783

Gnomad4 AMR exome

AF:

0.0766

Gnomad4 ASJ exome

AF:

0.139

Gnomad4 EAS exome

AF:

0.0159

Gnomad4 SAS exome

AF:

0.149

Gnomad4 FIN exome

AF:

0.103

Gnomad4 NFE exome

AF:

0.121

Gnomad4 OTH exome

AF:

0.116

GnomAD4 genome

AF:

0.102

AC:

15574

AN:

152204

Hom.:

894

Cov.:

AF XY:

0.102

AC XY:

7570

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0783

Gnomad4 AMR

AF:

0.0747

Gnomad4 ASJ

AF:

0.137

Gnomad4 EAS

AF:

0.0210

Gnomad4 SAS

AF:

0.153

Gnomad4 FIN

AF:

0.111

Gnomad4 NFE

AF:

0.122

Gnomad4 OTH

AF:

0.0843

Alfa

AF:

0.123

Hom.:

301

Bravo

AF:

0.0963

Asia WGS

AF:

0.0820

AC:

284

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Agenesis of the corpus callosum with peripheral neuropathy

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

7.5

DANN

Benign

0.32

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