rs1423014570

Variant names:

• chrX-135998550-C-T
• rs1423014570
• NM_001379110.1:c.516C>T

Variant summary

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

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
• Publications: 1 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, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379110.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	NM_001379110.1	MANE Select	c.516C>T	p.Phe172Phe	synonymous	Exon 5 of 18	NP_001366039.1	A0A0D9SGH0
	SLC9A6	NM_001438742.1		c.672C>T	p.Phe224Phe	synonymous	Exon 4 of 17	NP_001425671.1
	SLC9A6	NM_001042537.2		c.672C>T	p.Phe224Phe	synonymous	Exon 4 of 16	NP_001036002.1	Q92581-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	ENST00000630721.3	TSL:4 MANE Select	c.516C>T	p.Phe172Phe	synonymous	Exon 5 of 18	ENSP00000487486.2	A0A0D9SGH0
	SLC9A6	ENST00000370695.8	TSL:1	c.672C>T	p.Phe224Phe	synonymous	Exon 4 of 16	ENSP00000359729.4	Q92581-2
	SLC9A6	ENST00000370698.7	TSL:1	c.576C>T	p.Phe192Phe	synonymous	Exon 4 of 16	ENSP00000359732.3	Q92581-1

Frequencies

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

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

African (AFR) AF: 0.00 AC: 0 AN: 25379

American (AMR) AF: 0.00 AC: 0 AN: 33888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18845

East Asian (EAS) AF: 0.00 AC: 0 AN: 29559

South Asian (SAS) AF: 0.0000205 AC: 1 AN: 48802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40035

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3922

European-Non Finnish (NFE) AF: 0.00000870 AC: 7 AN: 804340

Other (OTH) AF: 0.00 AC: 0 AN: 44378

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

African (AFR) AF: 0.00 AC: 0 AN: 29536

American (AMR) AF: 0.00 AC: 0 AN: 10034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2613

East Asian (EAS) AF: 0.00 AC: 0 AN: 3480

South Asian (SAS) AF: 0.00 AC: 0 AN: 2568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5083

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.0000384 AC: 2 AN: 52150

Other (OTH) AF: 0.00 AC: 0 AN: 1437

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Christianson syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	6.3
DANN	Benign	0.78
PhyloP100		0.10
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1423014570; hg19: chrX-135080709; COSMIC: COSV65787749;