Genetic Variant NM_001379110.1:c.1081-8C>T (chrX-136016637-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_001379110.1(SLC9A6):c.1081-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,898 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene SLC9A6 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000068 ( 0 hom. 4 hem. )

Failed GnomAD Quality Control

Consequence

SLC9A6
NM_001379110.1 splice_region, intron

Scores

Splicing: ADA: 0.00002500

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.238

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, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, ClinGen

SLC9A6 links:

Genome browser will be placed here

ACMG classification

Specifications for SLC9A6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant X-136016637-C-T is Benign according to our data. Variant chrX-136016637-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 415899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379110.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC9A6	NM_001379110.1	MANE Select	c.1081-8C>T	splice_region intron	N/A	NP_001366039.1	A0A0D9SGH0
SLC9A6	NM_001438742.1		c.1237-8C>T	splice_region intron	N/A	NP_001425671.1
SLC9A6	NM_001042537.2		c.1237-8C>T	splice_region intron	N/A	NP_001036002.1	Q92581-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC9A6	ENST00000630721.3	TSL:4 MANE Select	c.1081-8C>T	splice_region intron	N/A	ENSP00000487486.2	A0A0D9SGH0
SLC9A6	ENST00000370695.8	TSL:1	c.1237-8C>T	splice_region intron	N/A	ENSP00000359729.4	Q92581-2
SLC9A6	ENST00000370698.7	TSL:1	c.1141-8C>T	splice_region intron	N/A	ENSP00000359732.3	Q92581-1

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000951

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000549

AC:

AN:

182155

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000682

AC:

AN:

879975

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

255915

show subpopulations

African (AFR)

AF:

0.0000448

AC:

AN:

22302

American (AMR)

AF:

0.0000287

AC:

AN:

34888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18001

East Asian (EAS)

AF:

0.00

AC:

AN:

29191

South Asian (SAS)

AF:

0.0000403

AC:

AN:

49639

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40365

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3686

European-Non Finnish (NFE)

AF:

0.00000311

AC:

AN:

643054

Other (OTH)

AF:

0.00

AC:

AN:

38849

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111898

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34078

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30800

American (AMR)

AF:

0.0000951

AC:

AN:

10517

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3585

South Asian (SAS)

AF:

0.00

AC:

AN:

2697

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53175

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Christianson syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.18

(source)

DANN

Benign

0.45

PhyloP100

-0.24

Mutation Taster

=43/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000025

dbscSNV1_RF

Benign

0.0020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over