chrX-135998163-A-G

Position:

• chrX-135998163-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001379110.1(SLC9A6):​c.425A>G​(p.Tyr142Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000268 in 1,118,243 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000020 (0 hom. 0 hem.)
• Consequence: SLC9A6 NM_001379110.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.74

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC9A6	NM_001379110.1	c.425A>G	p.Tyr142Cys	missense_variant	4/18	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3	c.425A>G	p.Tyr142Cys	missense_variant	4/18	4	NM_001379110.1	ENSP00000487486

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111917 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34061

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000946

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000199 AC: 2 AN: 1006326 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 299854

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000570

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111917 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34061

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000946

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Christianson syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Sep 26, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2023	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 162 of the SLC9A6 protein (p.Tyr162Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC9A6-related conditions. ClinVar contains an entry for this variant (Variation ID: 469636). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC9A6 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;.;.;.;.;.;.;T;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;.;D;.;.;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	.;.;.;.;.;.;.;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	.;.;.;.;.;D;D;D;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0020	.;.;.;.;.;D;D;D;.;.
Sift4G	Uncertain	0.0060	.;.;.;.;.;D;D;D;D;.
Polyphen		0.022, 0.013	.;.;.;.;.;.;B;B;.;.
Vest4		0.62, 0.64, 0.63
MutPred		0.63		.;.;.;.;.;.;.;Gain of sheet (P = 0.0827);.;.;
MVP		0.35
MPC		2.4
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.87
gMVP		0.77

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: rs1556616834; hg19: chrX-135080322;