Genetic Variant SLC9A6:p.Trp6Arg (chrX-135985518-T-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001438742.1(SLC9A6):c.16T>A(p.Trp6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000199 in 1,006,294 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 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. W6C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000020 ( 0 hom. 2 hem. )

Consequence

SLC9A6
NM_001438742.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.12

Publications

0 publications found

Variant links:

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

SLC9A6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2507657).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC9A6	NM_001379110.1	MANE Select	c.-57+41T>A		intron	N/A	NP_001366039.1	A0A0D9SGH0
SLC9A6	NM_001438742.1		c.16T>A	p.Trp6Arg	missense	Exon 1 of 17	NP_001425671.1
SLC9A6	NM_001042537.2		c.16T>A	p.Trp6Arg	missense	Exon 1 of 16	NP_001036002.1	Q92581-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC9A6	ENST00000370695.8	TSL:1	c.16T>A	p.Trp6Arg	missense	Exon 1 of 16	ENSP00000359729.4	Q92581-2
SLC9A6	ENST00000370698.7	TSL:1	c.16T>A	p.Trp6Arg	missense	Exon 1 of 16	ENSP00000359732.3	Q92581-1
SLC9A6	ENST00000630721.3	TSL:4 MANE Select	c.-57+41T>A		intron	N/A	ENSP00000487486.2	A0A0D9SGH0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000199

AC:

AN:

1006294

Hom.:

Cov.:

AF XY:

0.00000633

AC XY:

AN XY:

315772

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23115

American (AMR)

AF:

0.00

AC:

AN:

22934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15345

East Asian (EAS)

AF:

0.00

AC:

AN:

26825

South Asian (SAS)

AF:

0.00

AC:

AN:

43738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27433

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2828

European-Non Finnish (NFE)

AF:

0.00000249

AC:

AN:

801651

Other (OTH)

AF:

0.00

AC:

AN:

42425

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Christianson syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

PhyloP100

1.1

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.51

REVEL

Benign

0.18

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

0.0070

Vest4

0.29

MutPred

0.32

Gain of methylation at W6 (P = 0.002)

MVP

0.37

MPC

1.7

ClinPred

0.26

GERP RS

3.8

PromoterAI

-0.031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.41

gMVP

0.62

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over