rs796053286

Variant names:

• chrX-136013427-G-C
• rs796053286
• NM_001379110.1:c.1070G>C

Variant summary

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

The NM_001379110.1(SLC9A6):​c.1070G>C​(p.Arg357Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,063,098 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: SLC9A6 NM_001379110.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.32
• 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, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1	c.1070G>C	p.Arg357Thr	missense_variant	Exon 10 of 18	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3	c.1070G>C	p.Arg357Thr	missense_variant	Exon 10 of 18	4	NM_001379110.1	ENSP00000487486.2
SLC9A6	ENST00000370695.8	c.1226G>C	p.Arg409Thr	missense_variant	Exon 9 of 16	1		ENSP00000359729.4
SLC9A6	ENST00000370698.7	c.1130G>C	p.Arg377Thr	missense_variant	Exon 9 of 16	1		ENSP00000359732.3
SLC9A6	ENST00000370701.6	c.1070G>C	p.Arg357Thr	missense_variant	Exon 10 of 17	1		ENSP00000359735.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000282 AC: 3 AN: 1063098 Hom.: 0 Cov.: 26 AF XY: 0.00000302 AC XY: 1 AN XY: 331228

African (AFR) AF: 0.00 AC: 0 AN: 25781

American (AMR) AF: 0.00 AC: 0 AN: 35127

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19127

East Asian (EAS) AF: 0.00 AC: 0 AN: 29964

South Asian (SAS) AF: 0.00 AC: 0 AN: 53268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40355

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3852

European-Non Finnish (NFE) AF: 0.00000370 AC: 3 AN: 810698

Other (OTH) AF: 0.00 AC: 0 AN: 44926

GnomAD4 genome Cov.: 23

Alfa AF: 0.000187 Hom.: 1

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Sep 10, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	.;.;.;.;.;.;.;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;D;.;.;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.57	.;.;.;.;.;.;.;N;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	.;.;.;.;.;D;D;D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	.;.;.;.;.;D;D;D;.
Sift4G	Benign	0.15	.;.;.;.;.;T;T;T;.
Polyphen		0.18, 0.62	.;.;.;.;.;.;B;P;.
Vest4		0.83, 0.83, 0.84
MutPred		0.54		.;.;.;.;.;.;.;Gain of ubiquitination at K379 (P = 0.123);.;
MVP		0.85
MPC		2.6
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.89
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs796053286; hg19: chrX-135095586;