X-136012949-G-C

Variant names:

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

Variant summary

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

The NM_001379110.1(SLC9A6):​c.886G>C​(p.Val296Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V296M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC9A6 NM_001379110.1 missense, splice_region
• Scores: Splicing: ADA: 0.05378
• Clinical Significance: Not reported in ClinVar
• 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, SUPPORTIVE Submitted by: G2P, Orphanet, 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	NM_001379110.1	MANE Select	c.886G>C	p.Val296Leu	missense splice_region	Exon 9 of 18	NP_001366039.1
	SLC9A6	NM_001438742.1		c.1042G>C	p.Val348Leu	missense splice_region	Exon 8 of 17	NP_001425671.1
	SLC9A6	NM_001042537.2		c.1042G>C	p.Val348Leu	missense splice_region	Exon 8 of 16	NP_001036002.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	ENST00000630721.3	TSL:4 MANE Select	c.886G>C	p.Val296Leu	missense splice_region	Exon 9 of 18	ENSP00000487486.2
	SLC9A6	ENST00000370695.8	TSL:1	c.1042G>C	p.Val348Leu	missense splice_region	Exon 8 of 16	ENSP00000359729.4
	SLC9A6	ENST00000370698.7	TSL:1	c.946G>C	p.Val316Leu	missense splice_region	Exon 8 of 16	ENSP00000359732.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.087	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.11	N
PhyloP100		9.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	0.84	T
Polyphen		0.069	B
Vest4		0.68
MutPred		0.62		Gain of ubiquitination at K318 (P = 0.1245)
MVP		0.76
MPC		1.6
ClinPred		0.67	D
GERP RS		5.8
Varity_R		0.33
gMVP		0.82
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.054
SpliceAI score (max)		0.10		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;