rs151178361

Positions:

chrX-136016647-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BS2BP4BP7BP5_StrongBS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Leu381= variant in SLC9A6 (NM_006359.2) is 0.024% in European (Non-Finnish) sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Leu381= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Leu381= variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2_strong). The p.Leu381= variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx, internal database - Invitae) (BP5_strong). In summary, the p.Leu381= variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BS1, BP4, BP7, BS2_strong, BP5_strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10524772/MONDO:0010278/033

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 11 hem., cov: 22)

Exomes 𝑓: 0.00020 ( 0 hom. 56 hem. )

Consequence

SLC9A6
NM_001379110.1 splice_region, synonymous

Scores

2

Clinical Significance

Benign reviewed by expert panel U:1B:6

Conservation

PhyloP100: 2.15

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 -14 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC9A6	NM_001379110.1 linkuse as main transcript	c.1083G>A	p.Leu361=	splice_region_variant, synonymous_variant	11/18	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3 linkuse as main transcript	c.1083G>A	p.Leu361=	splice_region_variant, synonymous_variant	11/18	4	NM_001379110.1	ENSP00000487486

Frequencies

GnomAD3 genomes

AF:

0.000205

AC:

23

AN:

111993

Hom.:

0

Cov.:

22

AF XY:

0.000322

AC XY:

11

AN XY:

34163

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000664

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:

0.000263

Gnomad OTH

AF:

0.000663

GnomAD3 exomes

AF:

0.000148

AC:

27

AN:

182825

Hom.:

0

AF XY:

0.000163

AC XY:

11

AN XY:

67329

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000183

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:

0.000257

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000198

AC:

199

AN:

1004844

Hom.:

0

Cov.:

21

AF XY:

0.000184

AC XY:

56

AN XY:

304198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000143

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:

0.000246

Gnomad4 OTH exome

AF:

0.000186

GnomAD4 genome

AF:

0.000205

AC:

23

AN:

111993

Hom.:

0

Cov.:

22

AF XY:

0.000322

AC XY:

11

AN XY:

34163

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.000664

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000263

Gnomad4 OTH

AF:

0.000663

Alfa

AF:

0.000427

Hom.:

2

Bravo

AF:

0.000178

EpiCase

AF:

0.000600

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SLC9A6: BP4, BS2 -

Christianson syndrome

Benign:2

Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Feb 23, 2024	The allele frequency of the p.Leu381= variant in SLC9A6 (NM_006359.2) is 0.024% in European (Non-Finnish) sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Leu381= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Leu381= variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2_strong). The p.Leu381= variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx, internal database - Invitae) (BP5_strong). In summary, the p.Leu381= variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BS1, BP4, BP7, BS2_strong, BP5_strong). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 04, 2023	- -

SLC9A6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

History of neurodevelopmental disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2013

This alteration is classified as likely benign based on a combination of the following: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

15

DANN

Benign

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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.

Other links and lift over

dbSNP: rs151178361; hg19: chrX-135098806;