Genetic Variant ENST00000370695.8:c.8G>C (chrX-135985510-G-C) – 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>C(p.Arg3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000101 in 990,225 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. 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: 0.0000010 ( 0 hom. 0 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=0.13056219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1 link	c.-57+33G>C		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>C	p.Arg3Pro	missense_variant	Exon 1 of 16	1		ENSP00000359729.4	Q92581-2
SLC9A6	ENST00000370698.7 link	c.8G>C	p.Arg3Pro	missense_variant	Exon 1 of 16	1		ENSP00000359732.3	Q92581-1
SLC9A6	ENST00000630721.3 link	c.-57+33G>C		intron_variant	Intron 1 of 17	4	NM_001379110.1	ENSP00000487486.2	A0A0D9SGH0
SLC9A6	ENST00000370701.6 link	c.-57+33G>C		intron_variant	Intron 1 of 16	1		ENSP00000359735.1	Q92581-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000101

AC:

AN:

990225

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

310277

show subpopulations

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:

0.0000389

AC:

AN:

25686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2747

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

794122

Other (OTH)

AF:

0.00

AC:

AN:

41877

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.10

.;T

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.55

T;T

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L

PhyloP100

0.61

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.090

N;N

REVEL

Benign

0.040

Sift

Benign

0.059

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0

B;B

Vest4

0.19

MutPred

0.30

Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);

MVP

0.068

MPC

1.4

ClinPred

0.18

GERP RS

1.6

PromoterAI

0.16

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.11

gMVP

0.68

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over