X-135985527-G-T

Variant names:

• chrX-135985527-G-T
• rs201523857
• ENST00000370695.8:c.25G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ala9Ser variant in SLC9A6 is 0.307% in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). Computational analysis prediction tools suggest that the p.Ala9Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ala9Ser variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BA1, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA295170/MONDO:0010278/016

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., 107 hem., cov: 22)
  • Exomes 𝑓: 0.0045 (9 hom. 1447 hem.)
• Consequence: SLC9A6 NM_001438742.1 missense
• Clinical Significance: Benign reviewed by expert panel B:12
• Conservation: PhyloP100: 2.12
• Publications: 8 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: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438742.1. 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.-57+50G>T		intron	N/A	NP_001366039.1	A0A0D9SGH0
	SLC9A6	NM_001438742.1		c.25G>T	p.Ala9Ser	missense	Exon 1 of 17	NP_001425671.1
	SLC9A6	NM_001042537.2		c.25G>T	p.Ala9Ser	missense	Exon 1 of 16	NP_001036002.1	Q92581-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	ENST00000370695.8	TSL:1	c.25G>T	p.Ala9Ser	missense	Exon 1 of 16	ENSP00000359729.4	Q92581-2
	SLC9A6	ENST00000370698.7	TSL:1	c.25G>T	p.Ala9Ser	missense	Exon 1 of 16	ENSP00000359732.3	Q92581-1
	SLC9A6	ENST00000630721.3	TSL:4 MANE Select	c.-57+50G>T		intron	N/A	ENSP00000487486.2	A0A0D9SGH0

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 377 AN: 111153 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000377

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.00571

Gnomad OTH AF: 0.00469

GnomAD2 exomes AF: 0.00289 AC: 250 AN: 86554 AF XY: 0.00326

Gnomad AFR exome AF: 0.000776

Gnomad AMR exome AF: 0.000874

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00779

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.00445

GnomAD4 exome AF: 0.00452 AC: 4606 AN: 1019726 Hom.: 9 Cov.: 30 AF XY: 0.00452 AC XY: 1447 AN XY: 320406

African (AFR) AF: 0.000549 AC: 13 AN: 23701

American (AMR) AF: 0.00106 AC: 27 AN: 25522

Ashkenazi Jewish (ASJ) AF: 0.000126 AC: 2 AN: 15932

East Asian (EAS) AF: 0.0000365 AC: 1 AN: 27393

South Asian (SAS) AF: 0.000243 AC: 11 AN: 45254

European-Finnish (FIN) AF: 0.00828 AC: 239 AN: 28879

Middle Eastern (MID) AF: 0.00533 AC: 16 AN: 3004

European-Non Finnish (NFE) AF: 0.00512 AC: 4135 AN: 807130

Other (OTH) AF: 0.00378 AC: 162 AN: 42911

GnomAD4 genome AF: 0.00339 AC: 377 AN: 111193 Hom.: 1 Cov.: 22 AF XY: 0.00320 AC XY: 107 AN XY: 33427

African (AFR) AF: 0.000651 AC: 20 AN: 30702

American (AMR) AF: 0.00103 AC: 11 AN: 10654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3467

South Asian (SAS) AF: 0.000378 AC: 1 AN: 2644

European-Finnish (FIN) AF: 0.00603 AC: 36 AN: 5967

Middle Eastern (MID) AF: 0.00467 AC: 1 AN: 214

European-Non Finnish (NFE) AF: 0.00571 AC: 301 AN: 52727

Other (OTH) AF: 0.00463 AC: 7 AN: 1513

Alfa AF: 0.00216 Hom.: 14

Bravo AF: 0.00278

ExAC AF: 0.00263 AC: 297

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Christianson syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	1	Obesity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.095	T
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.037
Sift	Benign	0.11	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.20
MVP		0.15
MPC		0.95
ClinPred		0.0036	T
GERP RS		2.9
PromoterAI		0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.068
gMVP		0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs201523857; hg19: chrX-135067686; COSMIC: COSV65789170; COSMIC: COSV65789170;