rs587784400

Variant names:

• chrX-135994827-C-G
• rs587784400
• NM_001379110.1:c.211C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-135994827-C-G
• chrX-135994827-C-T

Variant summary

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

The NM_001379110.1(SLC9A6):​c.211C>G​(p.Pro71Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,022 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. P71L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SLC9A6 NM_001379110.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91
• 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.211C>G	p.Pro71Ala	missense_variant	Exon 3 of 18	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3	c.211C>G	p.Pro71Ala	missense_variant	Exon 3 of 18	4	NM_001379110.1	ENSP00000487486.2
SLC9A6	ENST00000370695.8	c.367C>G	p.Pro123Ala	missense_variant	Exon 2 of 16	1		ENSP00000359729.4
SLC9A6	ENST00000370698.7	c.367C>G	p.Pro123Ala	missense_variant	Exon 2 of 16	1		ENSP00000359732.3
SLC9A6	ENST00000370701.6	c.211C>G	p.Pro71Ala	missense_variant	Exon 3 of 17	1		ENSP00000359735.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098022 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363388

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

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54135

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841951

Other (OTH) AF: 0.00 AC: 0 AN: 46091

⚠️ 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.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 11, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;.;.;.;.;.;.;T;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	.;.;D;.;.;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;.;.;.;.;L;L;.;.
PhyloP100		2.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.2	.;.;.;.;.;N;N;D;.;.
REVEL	Benign	0.18
Sift	Benign	0.093	.;.;.;.;.;T;T;D;.;.
Sift4G	Benign	0.20	.;.;.;.;.;T;T;T;T;.
Polyphen		0.0010	.;.;.;.;.;.;B;B;.;.
Vest4		0.40, 0.44, 0.51
MutPred		0.68		.;.;.;.;.;.;Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);.;.;
MVP		0.48
MPC		1.0
ClinPred		0.71	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.90
Mutation Taster		=36/64	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: rs587784400; hg19: chrX-135076986;