X-135985673-C-G

Position:

chrX-135985673-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ile5Met variant in SLC9A6 is 0.013% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Ile5Met variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ile5Met variant in SLC9A6 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10524605/MONDO:0010278/016

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000041 ( 0 hom. 21 hem. )

Consequence

SLC9A6
NM_001379110.1 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:4

Conservation

PhyloP100: -0.100

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:

SLC9A6 (HGNC:):

SLC9A6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

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

BS1

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.15C>G	p.Ile5Met	missense_variant	2/18	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC9A6	ENST00000630721.3 linkuse as main transcript	c.15C>G	p.Ile5Met	missense_variant	2/18	4	NM_001379110.1	ENSP00000487486.2	A0A0D9SGH0
SLC9A6	ENST00000370695.8 linkuse as main transcript	c.171C>G	p.Ile57Met	missense_variant	1/16	1		ENSP00000359729.4	Q92581-2
SLC9A6	ENST00000370698.7 linkuse as main transcript	c.171C>G	p.Ile57Met	missense_variant	1/16	1		ENSP00000359732.3	Q92581-1
SLC9A6	ENST00000370701.6 linkuse as main transcript	c.15C>G	p.Ile5Met	missense_variant	2/17	1		ENSP00000359735.1	Q92581-3

Frequencies

GnomAD3 genomes

AF:

0.0000715

AC:

AN:

111855

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34029

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000151

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000382

AC:

AN:

183243

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

67737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000733

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1098201

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

363567

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000511

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000715

AC:

AN:

111855

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34029

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000151

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Christianson syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	The allele frequency of the p.Ile5Met variant in SLC9A6 is 0.013% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Ile5Met variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ile5Met variant in SLC9A6 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4). -
Likely benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Aug 29, 2019	This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: BS2,BP4. This variant was detected in hemizygous state. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SLC9A6: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2017	A variant of uncertain significance has been identified in the SLC9A6 gene. The I57M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I57M variant is observed in 3/47,771 alleles from individuals of European background, including multiple unrelated hemizygous individuals (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I57M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.15

.;.;.;.;.;.;.;T;T;.

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.83

.;.;T;.;.;T;T;T;T;T

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.11

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

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.9

.;.;.;.;.;.;L;L;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.55

.;.;.;.;.;N;N;N;.;.

REVEL

Benign

0.070

Sift

Benign

0.17

.;.;.;.;.;T;T;T;.;.

Sift4G

Benign

0.29

.;.;.;.;.;T;T;T;T;.

Polyphen

0.92, 0.41

.;.;.;.;.;.;P;B;.;.

Vest4

0.34, 0.31, 0.28

MutPred

0.27

.;.;.;.;.;.;Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);.;.;

MVP

0.29

MPC

1.1

ClinPred

0.038

GERP RS

0.32

Varity_R

0.15

gMVP

0.91

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