rs1016216648

Variant names:

• chrX-135985510-G-T
• rs1016216648
• ENST00000370695.8:c.8G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-135985510-G-T
• chrX-135985510-G-A
• chrX-135985510-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001438742.1(SLC9A6):​c.8G>T​(p.Arg3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000363 in 1,101,352 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000030 (0 hom. 0 hem.)
• Consequence: SLC9A6 NM_001438742.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.608
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13352051).

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+33G>T		intron	N/A	NP_001366039.1	A0A0D9SGH0
	SLC9A6	NM_001438742.1		c.8G>T	p.Arg3Leu	missense	Exon 1 of 17	NP_001425671.1
	SLC9A6	NM_001042537.2		c.8G>T	p.Arg3Leu	missense	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.8G>T	p.Arg3Leu	missense	Exon 1 of 16	ENSP00000359729.4	Q92581-2
	SLC9A6	ENST00000370698.7	TSL:1	c.8G>T	p.Arg3Leu	missense	Exon 1 of 16	ENSP00000359732.3	Q92581-1
	SLC9A6	ENST00000630721.3	TSL:4 MANE Select	c.-57+33G>T		intron	N/A	ENSP00000487486.2	A0A0D9SGH0

Frequencies

GnomAD3 genomes AF: 0.00000900 AC: 1 AN: 111127 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000190

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000303 AC: 3 AN: 990225 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 310277

African (AFR) AF: 0.00 AC: 0 AN: 22515

American (AMR) AF: 0.00 AC: 0 AN: 20657

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14862

East Asian (EAS) AF: 0.00 AC: 0 AN: 25848

South Asian (SAS) AF: 0.00 AC: 0 AN: 41911

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2747

European-Non Finnish (NFE) AF: 0.00000378 AC: 3 AN: 794122

Other (OTH) AF: 0.00 AC: 0 AN: 41877

GnomAD4 genome AF: 0.00000900 AC: 1 AN: 111127 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33391

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30617

American (AMR) AF: 0.00 AC: 0 AN: 10624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3477

South Asian (SAS) AF: 0.00 AC: 0 AN: 2665

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5975

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000190 AC: 1 AN: 52734

Other (OTH) AF: 0.00 AC: 0 AN: 1485

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	Benign	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.61
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.053
Sift	Benign	0.17	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.20
MutPred		0.30		Loss of solvent accessibility (P = 0.1144)
MVP		0.068
MPC		1.3
ClinPred		0.27	T
GERP RS		1.6
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.058
gMVP		0.63
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1016216648; hg19: chrX-135067669;