rs2307131

chrX-136040103-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379110.1(SLC9A6):c.1689C>T(p.Ser563=) 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:7
• Conservation: PhyloP100: -1.49

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 139209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136040103-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
SLC9A6	NM_001379110.1	c.1689C>T	p.Ser563=	synonymous_variant	17/18	ENST00000630721.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC9A6	ENST00000630721.3	c.1689C>T	p.Ser563=	synonymous_variant	17/18	4	NM_001379110.1

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 3362 AN: 112124 Hom.: 43 Cov.: 23 AF XY: 0.0295 AC XY: 1012 AN XY: 34274

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

GnomAD3 exomes AF: 0.0359 AC: 6490 AN: 180631 Hom.: 92 AF XY: 0.0402 AC XY: 2630 AN XY: 65353

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 SAS exome AF: 0.106

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

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.00788

Gnomad4 ASJ exome AF: 0.0268

Gnomad4 EAS exome AF: 0.0810

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0333

Gnomad4 NFE exome AF: 0.0291

Gnomad4 OTH exome AF: 0.0323

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

Gnomad4 AFR AF: 0.0296

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.0241

Gnomad4 EAS AF: 0.0792

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.0288

Gnomad4 NFE AF: 0.0273

Gnomad4 OTH AF: 0.0216

Alfa AF: 0.0291 Hom.: 392

Bravo AF: 0.0278

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 06, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2012	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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2015

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. -

Christianson syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.063
Dann	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs2307131; hg19: chrX-135122262;