X-135985504-T-G

Variant names:

• chrX-135985504-T-G
• rs1006154022
• ENST00000370695.8:c.2T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_Supporting PVS1_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Met1? variant in SLC9A6 may cause a truncated or absent protein by altering the start codon of the coding sequence, however, to date, there is no additional evidence to support that the loss of this methionine is associated with disease (PVS1_supporting). The p.Met1? variant in SLC9A6 is absent from gnomAD (PM2_supporting). In summary, the p.Met1? variant in SLC9A6 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PVS1_supporting, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16608696/MONDO:0010278/016

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000017 (0 hom. 5 hem.)
• Consequence: SLC9A6 NM_001438742.1 start_lost
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 1.01
• 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.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438742.1. 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.-57+27T>G		intron	N/A	NP_001366039.1	A0A0D9SGH0
	SLC9A6	NM_001438742.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 17	NP_001425671.1
	SLC9A6	NM_001042537.2		c.2T>G	p.Met1?	start_lost	Exon 1 of 16	NP_001036002.1	Q92581-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	ENST00000370695.8	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 16	ENSP00000359729.4	Q92581-2
	SLC9A6	ENST00000370698.7	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 16	ENSP00000359732.3	Q92581-1
	SLC9A6	ENST00000630721.3	TSL:4 MANE Select	c.-57+27T>G		intron	N/A	ENSP00000487486.2	A0A0D9SGH0

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000202 AC: 1 AN: 49564 AF XY: 0.00

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: 0.0000476

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 17 AN: 982839 Hom.: 0 Cov.: 29 AF XY: 0.0000162 AC XY: 5 AN XY: 308177

African (AFR) AF: 0.00 AC: 0 AN: 22092

American (AMR) AF: 0.00 AC: 0 AN: 19421

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14574

East Asian (EAS) AF: 0.00 AC: 0 AN: 25598

South Asian (SAS) AF: 0.00 AC: 0 AN: 41279

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25213

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2703

European-Non Finnish (NFE) AF: 0.0000215 AC: 17 AN: 790427

Other (OTH) AF: 0.00 AC: 0 AN: 41532

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Christianson syndrome (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.096	T
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.96	T
PhyloP100		1.0
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.77
MutPred		0.86		Gain of methylation at M1 (P = 0.031)
MVP		0.97
ClinPred		0.90	D
GERP RS		3.7
PromoterAI		-0.14	Neutral
Varity_R		0.91
gMVP		0.87
Mutation Taster		=72/128	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1006154022; hg19: chrX-135067663;