dbSNP rs1016216648: SLC9A6:p.Arg3Gln (chrX-135985510-G-A) – 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 ENST00000370695.8(SLC9A6):c.8G>A(p.Arg3Gln) 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 990,223 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. 13/21 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
ENST00000370695.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.608

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, SUPPORTIVE Submitted by: G2P, Orphanet, 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=0.131311).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1 link	c.-57+33G>A		intron_variant	Intron 1 of 17	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC9A6	ENST00000370695.8 link	c.8G>A	p.Arg3Gln	missense_variant	Exon 1 of 16	1		ENSP00000359729.4	Q92581-2
SLC9A6	ENST00000370698.7 link	c.8G>A	p.Arg3Gln	missense_variant	Exon 1 of 16	1		ENSP00000359732.3	Q92581-1
SLC9A6	ENST00000630721.3 link	c.-57+33G>A		intron_variant	Intron 1 of 17	4	NM_001379110.1	ENSP00000487486.2	A0A0D9SGH0
SLC9A6	ENST00000370701.6 link	c.-57+33G>A		intron_variant	Intron 1 of 16	1		ENSP00000359735.1	Q92581-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000202

AC:

AN:

990223

Hom.:

Cov.:

AF XY:

0.00000322

AC XY:

AN XY:

310275

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

22515

American (AMR)

AF:

0.00

AC:

AN:

20657

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14862

East Asian (EAS)

AF:

0.00

AC:

AN:

25848

South Asian (SAS)

AF:

0.00

AC:

AN:

41911

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2746

European-Non Finnish (NFE)

AF:

0.00000126

AC:

AN:

794121

Other (OTH)

AF:

0.0000239

AC:

AN:

41877

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;T

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.75

T;T

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L

PhyloP100

0.61

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.090

N;N

REVEL

Benign

0.020

Sift

Benign

0.13

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.20

B;B

Vest4

0.20

MutPred

0.29

Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);

MVP

0.12

MPC

1.2

ClinPred

0.33

GERP RS

1.6

PromoterAI

-0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.041

gMVP

0.54

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over