chrX-135985771-T-C

Variant names:

• chrX-135985771-T-C
• rs1556614843
• NM_001379110.1:c.113T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001379110.1(SLC9A6):​c.113T>C​(p.Leu38Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SLC9A6 NM_001379110.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.65
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1	c.113T>C	p.Leu38Pro	missense_variant	Exon 2 of 18	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3	c.113T>C	p.Leu38Pro	missense_variant	Exon 2 of 18	4	NM_001379110.1	ENSP00000487486.2
SLC9A6	ENST00000370695.8	c.269T>C	p.Leu90Pro	missense_variant	Exon 1 of 16	1		ENSP00000359729.4
SLC9A6	ENST00000370698.7	c.269T>C	p.Leu90Pro	missense_variant	Exon 1 of 16	1		ENSP00000359732.3
SLC9A6	ENST00000370701.6	c.113T>C	p.Leu38Pro	missense_variant	Exon 2 of 17	1		ENSP00000359735.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Christianson syndrome Uncertain:1

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 90 of the SLC9A6 protein (p.Leu90Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC9A6-related conditions. ClinVar contains an entry for this variant (Variation ID: 469635). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;.;.;.;.;.;.;T;T;.
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	.;.;D;.;.;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	3.6	.;.;.;.;.;.;H;H;.;.
PhyloP100		5.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	.;.;.;.;.;D;D;D;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0040	.;.;.;.;.;D;D;D;.;.
Sift4G	Uncertain	0.012	.;.;.;.;.;D;D;D;D;.
Polyphen		1.0	.;.;.;.;.;.;D;D;.;.
Vest4		0.93, 0.93, 0.92
MutPred		0.81		.;.;.;.;.;.;Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);.;.;
MVP		0.87
MPC		2.7
ClinPred		0.98	D
GERP RS		3.7
PromoterAI		0.079	Neutral
Varity_R		0.95
gMVP		1.0
Mutation Taster		=31/69	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: rs1556614843; hg19: chrX-135067930;