rs146263125

Positions:

chrX-136033469-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001379110.1(SLC9A6):c.1637G>A(p.Arg546Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,172,230 control chromosomes in the GnomAD database, including 2 homozygotes. There are 751 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R546W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., 45 hem., cov: 22)

Exomes 𝑓: 0.0022 ( 1 hom. 706 hem. )

Consequence

SLC9A6
NM_001379110.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 9.60

Variant links:

Genes affected

SLC9A6 (HGNC:11079): (solute carrier family 9 member A6) This gene encodes a sodium-hydrogen exchanger that is amember of the solute carrier family 9. The encoded protein localizes to early and recycling endosomes and may be involved in regulating endosomal pH and volume. Defects in this gene are associated with X-linked syndromic cognitive disability, Christianson type. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

SLC9A6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant X-136033469-G-A is Benign according to our data. Variant chrX-136033469-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 139207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136033469-G-A is described in Lovd as [Likely_benign]. Variant chrX-136033469-G-A is described in Lovd as [Benign].

BS2

High Hemizygotes in GnomAd4 at 45 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC9A6	NM_001379110.1 linkuse as main transcript	c.1637G>A	p.Arg546Gln	missense_variant	16/18	ENST00000630721.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC9A6	ENST00000630721.3 linkuse as main transcript	c.1637G>A	p.Arg546Gln	missense_variant	16/18	4	NM_001379110.1

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

172

AN:

110521

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

AN XY:

32799

show subpopulations

Gnomad AFR

AF:

0.000494

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00192

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:

0.00255

Gnomad OTH

AF:

0.00134

GnomAD3 exomes

AF:

0.00166

AC:

304

AN:

182996

Hom.:

AF XY:

0.00161

AC XY:

109

AN XY:

67526

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.00106

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.000315

Gnomad NFE exome

AF:

0.00311

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

AF:

0.00221

AC:

2349

AN:

1061659

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

706

AN XY:

332559

show subpopulations

Gnomad4 AFR exome

AF:

0.000429

Gnomad4 AMR exome

AF:

0.000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000751

Gnomad4 FIN exome

AF:

0.000335

Gnomad4 NFE exome

AF:

0.00272

Gnomad4 OTH exome

AF:

0.00162

GnomAD4 genome

AF:

0.00156

AC:

172

AN:

110571

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

AN XY:

32859

show subpopulations

Gnomad4 AFR

AF:

0.000493

Gnomad4 AMR

AF:

0.00192

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00255

Gnomad4 OTH

AF:

0.00133

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00133

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00312

AC:

ExAC

AF:

0.00158

AC:

192

EpiCase

AF:

0.00191

EpiControl

AF:

0.00202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2014	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 12, 2015	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Christianson syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.021

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.60

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

Polyphen

0.92, 0.98

.;.;.;.;.;.;P;D;.;.

Vest4

0.42, 0.32, 0.56

MVP

0.74

MPC

2.3

ClinPred

0.044

GERP RS

5.2

Varity_R

0.84

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.30

Position offset: 24

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