NM_001379110.1:c.1083G>A

Variant names:

• chrX-136016647-G-A
• rs151178361
• NM_001379110.1:c.1083G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BS2 BP4 BP7 BP5_Strong BS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Leu381= variant in SLC9A6 (NM_006359.2) is 0.024% in European (Non-Finnish) sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Leu381= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Leu381= variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2_strong). The p.Leu381= variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx, internal database - Invitae) (BP5_strong). In summary, the p.Leu381= variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BS1, BP4, BP7, BS2_strong, BP5_strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10524772/MONDO:0010278/033

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 11 hem., cov: 22)
  • Exomes 𝑓: 0.00020 (0 hom. 56 hem.)
• Consequence: SLC9A6 NM_001379110.1 splice_region, synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1	c.1083G>A	p.Leu361Leu	splice_region_variant, synonymous_variant	Exon 11 of 18	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3	c.1083G>A	p.Leu361Leu	splice_region_variant, synonymous_variant	Exon 11 of 18	4	NM_001379110.1	ENSP00000487486.2
SLC9A6	ENST00000370695.8	c.1239G>A	p.Leu413Leu	splice_region_variant, synonymous_variant	Exon 10 of 16	1		ENSP00000359729.4
SLC9A6	ENST00000370698.7	c.1143G>A	p.Leu381Leu	splice_region_variant, synonymous_variant	Exon 10 of 16	1		ENSP00000359732.3
SLC9A6	ENST00000370701.6	c.1083G>A	p.Leu361Leu	splice_region_variant, synonymous_variant	Exon 11 of 17	1		ENSP00000359735.1

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 23 AN: 111993 Hom.: 0 Cov.: 22 AF XY: 0.000322 AC XY: 11 AN XY: 34163

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.000663

GnomAD3 exomes AF: 0.000148 AC: 27 AN: 182825 Hom.: 0 AF XY: 0.000163 AC XY: 11 AN XY: 67329

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000198 AC: 199 AN: 1004844 Hom.: 0 Cov.: 21 AF XY: 0.000184 AC XY: 56 AN XY: 304198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.000186

GnomAD4 genome AF: 0.000205 AC: 23 AN: 111993 Hom.: 0 Cov.: 22 AF XY: 0.000322 AC XY: 11 AN XY: 34163

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.000664

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000263

Gnomad4 OTH AF: 0.000663

Alfa AF: 0.000427 Hom.: 2

Bravo AF: 0.000178

EpiCase AF: 0.000600

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:2

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC9A6: BP4, BS2 -

Oct 14, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Christianson syndrome Benign:2

Feb 23, 2024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the p.Leu381= variant in SLC9A6 (NM_006359.2) is 0.024% in European (Non-Finnish) sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Leu381= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Leu381= variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2_strong). The p.Leu381= variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx, internal database - Invitae) (BP5_strong). In summary, the p.Leu381= variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BS1, BP4, BP7, BS2_strong, BP5_strong). -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SLC9A6-related disorder Benign:1

Nov 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

History of neurodevelopmental disorder Benign:1

Oct 18, 2013

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs151178361; hg19: chrX-135098806;