rs1556619324

Variant names:

• chrX-136016754-C-A
• rs1556619324
• NM_001379110.1:c.1190C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001379110.1(SLC9A6):​c.1190C>A​(p.Ala397Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC9A6 NM_001379110.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

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.1190C>A	p.Ala397Glu	missense	Exon 11 of 18	NP_001366039.1
	SLC9A6	NM_001438742.1		c.1346C>A	p.Ala449Glu	missense	Exon 10 of 17	NP_001425671.1
	SLC9A6	NM_001042537.2		c.1346C>A	p.Ala449Glu	missense	Exon 10 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.1190C>A	p.Ala397Glu	missense	Exon 11 of 18	ENSP00000487486.2
	SLC9A6	ENST00000370695.8	TSL:1	c.1346C>A	p.Ala449Glu	missense	Exon 10 of 16	ENSP00000359729.4
	SLC9A6	ENST00000370698.7	TSL:1	c.1250C>A	p.Ala417Glu	missense	Exon 10 of 16	ENSP00000359732.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 919678 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 249822

African (AFR) AF: 0.00 AC: 0 AN: 23009

American (AMR) AF: 0.00 AC: 0 AN: 33840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18037

East Asian (EAS) AF: 0.00 AC: 0 AN: 29371

South Asian (SAS) AF: 0.00 AC: 0 AN: 48573

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3729

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 682671

Other (OTH) AF: 0.00 AC: 0 AN: 40052

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Amblyopia;C0004106:Astigmatism;C0020490:Hypermetropia;C0020517:Allergy;C0023520:Leukodystrophy;C0036572:Seizure;C0038379:Strabismus;C0240379:Open mouth;C0349588:Short stature;C0454644:Delayed speech and language development;C1854301:Motor delay;C4021217:EEG with generalized slow activity;C4551563:Microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.77		Loss of glycosylation at T412 (P = 0.2445)
MVP		0.76
MPC		2.4
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		1.0
Mutation Taster		=34/66	disease causing

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: rs1556619324; hg19: chrX-135098913;