rs1556618832

chrX-136012949-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001379110.1(SLC9A6):c.886G>A(p.Val296Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000185 in 1,081,549 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: SLC9A6 NM_001379110.1 missense, splice_region
• Scores: Splicing: ADA: 0.9976
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC9A6	NM_001379110.1	c.886G>A	p.Val296Met	missense_variant, splice_region_variant	9/18	ENST00000630721.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC9A6	ENST00000630721.3	c.886G>A	p.Val296Met	missense_variant, splice_region_variant	9/18	4	NM_001379110.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183486 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1081549 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 348555

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000242

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Christianson syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 316 of the SLC9A6 protein (p.Val316Met). This variant is present in population databases (no rsID available, gnomAD 0.001%), including at least one homozygous and/or hemizygous individual. 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: 469638). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	29
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
Polyphen		0.86, 0.23	.;.;.;.;.;.;P;B;.
Vest4		0.64, 0.65, 0.68
MutPred		0.64		.;.;.;.;.;.;.;Gain of ubiquitination at K318 (P = 0.0817);.;
MVP		0.81
MPC		2.1
ClinPred		0.63	D
GERP RS		5.8
Varity_R		0.31
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.040		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: rs1556618832; hg19: chrX-135095108; COSMIC: COSV65788420;