rs1423014570

Positions:

• chrX-135998550-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. BS2 PM2_Supporting BP4 BP7

This summary comes from the ClinGen Evidence Repository: The p.Phe192= variant in SLC9A6 (NM_006359.2) is observed in the hemizygous state in at least 3 unaffected individuals (internal database - GeneDx) (BS2). The p.Phe172= variant in SLC9A6 is absent from gnomAD (PM2_Supporting). The silent p.Phe172= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in 3 unaffected hemizygous individuals, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion and classified the p.Phe192= variant in SLC9A6 as Likely Benign (BS2, BP4, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA518744234/MONDO:0010278/033

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000076 (0 hom. 1 hem.)
• Consequence: SLC9A6 NM_001379110.1 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:3
• Conservation: PhyloP100: 0.104

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 Likely_benign. Variant got -5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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	c.516C>T	p.Phe172=	synonymous_variant	5/18	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3	c.516C>T	p.Phe172=	synonymous_variant	5/18	4	NM_001379110.1	ENSP00000487486

Frequencies

GnomAD3 genomes AF: 0.0000186 AC: 2 AN: 107808 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31028

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: 0.0000384

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000763 AC: 8 AN: 1049148 Hom.: 0 Cov.: 26 AF XY: 0.00000310 AC XY: 1 AN XY: 322382

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: 0.0000205

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000870

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000186 AC: 2 AN: 107808 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31028

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: 0.0000384

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Christianson syndrome Benign:2

Likely benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 13, 2023	The p.Phe192= variant in SLC9A6 (NM_006359.2) is observed in the hemizygous state in at least 3 unaffected individuals (internal database - GeneDx) (BS2). The p.Phe172= variant in SLC9A6 is absent from gnomAD (PM2_Supporting). The silent p.Phe172= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in 3 unaffected hemizygous individuals, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion and classified the p.Phe192= variant in SLC9A6 as Likely Benign (BS2, BP4, BP7). -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 06, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 30, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	6.3
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1423014570; hg19: chrX-135080709; COSMIC: COSV65787749;