rs2307131

Variant names:

• chrX-136040103-C-T
• rs2307131
• NM_001379110.1:c.1689C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379110.1(SLC9A6):​c.1689C>T​(p.Ser563Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0335 in 1,208,581 control chromosomes in the GnomAD database, including 571 homozygotes. There are 14,130 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (43 hom., 1014 hem., cov: 23)
  • Exomes 𝑓: 0.034 (528 hom. 13116 hem.)
• Consequence: SLC9A6 NM_001379110.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.49
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-136040103-C-T is Benign according to our data. Variant chrX-136040103-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1	c.1689C>T	p.Ser563Ser	synonymous_variant	Exon 17 of 18	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3	c.1689C>T	p.Ser563Ser	synonymous_variant	Exon 17 of 18	4	NM_001379110.1	ENSP00000487486.2
SLC9A6	ENST00000370695.8	c.1755C>T	p.Ser585Ser	synonymous_variant	Exon 15 of 16	1		ENSP00000359729.4
SLC9A6	ENST00000370698.7	c.1659C>T	p.Ser553Ser	synonymous_variant	Exon 15 of 16	1		ENSP00000359732.3
SLC9A6	ENST00000370701.6	c.1599C>T	p.Ser533Ser	synonymous_variant	Exon 16 of 17	1		ENSP00000359735.1

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 3362 AN: 112124 Hom.: 43 Cov.: 23

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00979

Gnomad ASJ AF: 0.0241

Gnomad EAS AF: 0.0794

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.0212

GnomAD2 exomes AF: 0.0359 AC: 6490 AN: 180631 AF XY: 0.0402

Gnomad AFR exome AF: 0.0329

Gnomad AMR exome AF: 0.00763

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.0685

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0262

Gnomad OTH exome AF: 0.0323

GnomAD4 exome AF: 0.0338 AC: 37086 AN: 1096406 Hom.: 528 Cov.: 29 AF XY: 0.0362 AC XY: 13116 AN XY: 361964

African (AFR) AF: 0.0291 AC: 768 AN: 26371

American (AMR) AF: 0.00788 AC: 277 AN: 35144

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 519 AN: 19370

East Asian (EAS) AF: 0.0810 AC: 2443 AN: 30173

South Asian (SAS) AF: 0.106 AC: 5691 AN: 53934

European-Finnish (FIN) AF: 0.0333 AC: 1346 AN: 40455

Middle Eastern (MID) AF: 0.0149 AC: 61 AN: 4081

European-Non Finnish (NFE) AF: 0.0291 AC: 24496 AN: 840874

Other (OTH) AF: 0.0323 AC: 1485 AN: 46004

GnomAD4 genome AF: 0.0300 AC: 3365 AN: 112175 Hom.: 43 Cov.: 23 AF XY: 0.0295 AC XY: 1014 AN XY: 34335

African (AFR) AF: 0.0296 AC: 917 AN: 30957

American (AMR) AF: 0.00987 AC: 105 AN: 10637

Ashkenazi Jewish (ASJ) AF: 0.0241 AC: 64 AN: 2652

East Asian (EAS) AF: 0.0792 AC: 281 AN: 3550

South Asian (SAS) AF: 0.118 AC: 310 AN: 2634

European-Finnish (FIN) AF: 0.0288 AC: 175 AN: 6083

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 217

European-Non Finnish (NFE) AF: 0.0273 AC: 1456 AN: 53237

Other (OTH) AF: 0.0216 AC: 33 AN: 1525

Alfa AF: 0.0287 Hom.: 609

Bravo AF: 0.0278

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 06, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Benign:1

Sep 25, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Christianson syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.063
DANN	Benign	0.67
PhyloP100		-1.5
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2307131; hg19: chrX-135122262;