chrX-136012949-G-A

Variant names:

• chrX-136012949-G-A
• rs1556618832
• NM_001379110.1:c.886G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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. 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
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.886G>A	p.Val296Met	missense splice_region	Exon 9 of 18	NP_001366039.1	A0A0D9SGH0
	SLC9A6	NM_001438742.1		c.1042G>A	p.Val348Met	missense splice_region	Exon 8 of 17	NP_001425671.1
	SLC9A6	NM_001042537.2		c.1042G>A	p.Val348Met	missense splice_region	Exon 8 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.886G>A	p.Val296Met	missense splice_region	Exon 9 of 18	ENSP00000487486.2	A0A0D9SGH0
	SLC9A6	ENST00000370695.8	TSL:1	c.1042G>A	p.Val348Met	missense splice_region	Exon 8 of 16	ENSP00000359729.4	Q92581-2
	SLC9A6	ENST00000370698.7	TSL:1	c.946G>A	p.Val316Met	missense splice_region	Exon 8 of 16	ENSP00000359732.3	Q92581-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183486 AF XY: 0.0000147

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26077

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19276

East Asian (EAS) AF: 0.00 AC: 0 AN: 30138

South Asian (SAS) AF: 0.00 AC: 0 AN: 53756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4099

European-Non Finnish (NFE) AF: 0.00000242 AC: 2 AN: 826944

Other (OTH) AF: 0.00 AC: 0 AN: 45554

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Christianson syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		9.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.28
Sift	Benign	0.28	T
Sift4G	Benign	0.29	T
Polyphen		0.86	P
Vest4		0.64
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
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs1556618832; hg19: chrX-135095108; COSMIC: COSV65788420;