rs587784401

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001379110.1(SLC9A6):c.256A>G(p.Ser86Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000414 in 1,207,043 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000037 ( 0 hom. 2 hem. )

Consequence

SLC9A6
NM_001379110.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.89

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Christianson syndrome
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen

SLC9A6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21406034).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000365 (4/1095077) while in subpopulation EAS AF = 0.0000994 (3/30193). AF 95% confidence interval is 0.0000263. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1 link	c.256A>G	p.Ser86Gly	missense_variant	Exon 3 of 18	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC9A6	ENST00000630721.3 link	c.256A>G	p.Ser86Gly	missense_variant	Exon 3 of 18	4	NM_001379110.1	ENSP00000487486.2	A0A0D9SGH0
SLC9A6	ENST00000370695.8 link	c.412A>G	p.Ser138Gly	missense_variant	Exon 2 of 16	1		ENSP00000359729.4	Q92581-2
SLC9A6	ENST00000370698.7 link	c.412A>G	p.Ser138Gly	missense_variant	Exon 2 of 16	1		ENSP00000359732.3	Q92581-1
SLC9A6	ENST00000370701.6 link	c.256A>G	p.Ser86Gly	missense_variant	Exon 3 of 17	1		ENSP00000359735.1	Q92581-3

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111913

Hom.:

Cov.:

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:

0.000279

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183493

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000721

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1095077

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

360459

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26348

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19366

East Asian (EAS)

AF:

0.0000994

AC:

AN:

30193

South Asian (SAS)

AF:

0.00

AC:

AN:

54074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839232

Other (OTH)

AF:

0.0000217

AC:

AN:

45993

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111966

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30853

American (AMR)

AF:

0.00

AC:

AN:

10512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.000279

AC:

AN:

3580

South Asian (SAS)

AF:

0.00

AC:

AN:

2674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53262

Other (OTH)

AF:

0.00

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Christianson syndrome

Uncertain:2

Jun 10, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 138 of the SLC9A6 protein (p.Ser138Gly). This variant is present in population databases (rs587784401, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SLC9A6-related conditions. ClinVar contains an entry for this variant (Variation ID: 159935). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC9A6 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Aug 08, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC9A6 c.412A>G (p.Ser138Gly) results in a non-conservative amino acid change located in the Cation/H+ exchanger domain (IPR006153) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-06 in 183493 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.412A>G in individuals affected with Christianson Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 159935). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC9A6: PM2, BP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

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

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

.;.;D;.;.;D;D;D;D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.21

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.64

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

PhyloP100

5.9

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.24

Sift

Benign

0.25

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

Sift4G

Benign

0.31

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

Polyphen

0.0020

.;.;.;.;.;.;B;B;.;.

Vest4

0.35, 0.36

MutPred

0.57

.;.;.;.;.;.;Loss of glycosylation at S138 (P = 0.029);Loss of glycosylation at S138 (P = 0.029);.;.;

MVP

0.68

MPC

1.7

ClinPred

0.50

GERP RS

5.1

Varity_R

0.53

gMVP

0.84

Mutation Taster

=47/53

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over