Genetic Variant SLC9A6:p.Arg3Gly (chrX-135985509-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001438742.1(SLC9A6):c.7C>G(p.Arg3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000202 in 991,574 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. 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. R3W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000020 ( 0 hom. 1 hem. )

Consequence

SLC9A6
NM_001438742.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.455

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: 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=0.112602204).

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+32C>G		intron	N/A	NP_001366039.1	A0A0D9SGH0
SLC9A6	NM_001438742.1		c.7C>G	p.Arg3Gly	missense	Exon 1 of 17	NP_001425671.1
SLC9A6	NM_001042537.2		c.7C>G	p.Arg3Gly	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.7C>G	p.Arg3Gly	missense	Exon 1 of 16	ENSP00000359729.4	Q92581-2
SLC9A6	ENST00000370698.7	TSL:1	c.7C>G	p.Arg3Gly	missense	Exon 1 of 16	ENSP00000359732.3	Q92581-1
SLC9A6	ENST00000630721.3	TSL:4 MANE Select	c.-57+32C>G		intron	N/A	ENSP00000487486.2	A0A0D9SGH0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000177

AC:

AN:

56485

AF XY:

0.000123

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000503

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000202

AC:

AN:

991574

Hom.:

Cov.:

AF XY:

0.00000321

AC XY:

AN XY:

311118

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22637

American (AMR)

AF:

0.00

AC:

AN:

20925

Ashkenazi Jewish (ASJ)

AF:

0.000134

AC:

AN:

14911

East Asian (EAS)

AF:

0.00

AC:

AN:

26060

South Asian (SAS)

AF:

0.00

AC:

AN:

42220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

794317

Other (OTH)

AF:

0.00

AC:

AN:

41928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

0.46

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.31

REVEL

Benign

0.059

Sift

Benign

0.15

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.16

MutPred

0.35

Gain of relative solvent accessibility (P = 0.0275)

MVP

0.11

MPC

1.3

ClinPred

0.16

GERP RS

3.1

PromoterAI

-0.059

Neutral

(source)

Varity_R

0.15

gMVP

0.69

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over