NM_001379110.1:c.1662-4G>A

Variant names:

• chrX-136040072-G-A
• rs188072063
• NM_001379110.1:c.1662-4G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379110.1(SLC9A6):​c.1662-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,197,139 control chromosomes in the GnomAD database, including 45 homozygotes. There are 4,024 hemizygotes 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 Benign (★★). The gene SLC9A6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0070 (4 hom., 221 hem., cov: 24)
  • Exomes 𝑓: 0.011 (41 hom. 3803 hem.)
• Consequence: SLC9A6 NM_001379110.1 splice_region, intron
• Scores: Splicing: ADA: 0.00006198
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.23
• Publications: 2 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, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, ClinGen

ACMG classification

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-136040072-G-A is Benign according to our data. Variant chrX-136040072-G-A is described in ClinVar as Benign. ClinVar VariationId is 139208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00702 (787/112106) while in subpopulation NFE AF = 0.0114 (606/53238). AF 95% confidence interval is 0.0106. There are 4 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	NM_001379110.1	MANE Select	c.1662-4G>A		splice_region intron	N/A	NP_001366039.1	A0A0D9SGH0
	SLC9A6	NM_001438742.1		c.1818-4G>A		splice_region intron	N/A	NP_001425671.1
	SLC9A6	NM_001042537.2		c.1728-4G>A		splice_region intron	N/A	NP_001036002.1	Q92581-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	ENST00000630721.3	TSL:4 MANE Select	c.1662-4G>A		splice_region intron	N/A	ENSP00000487486.2	A0A0D9SGH0
	SLC9A6	ENST00000370695.8	TSL:1	c.1728-4G>A		splice_region intron	N/A	ENSP00000359729.4	Q92581-2
	SLC9A6	ENST00000370698.7	TSL:1	c.1632-4G>A		splice_region intron	N/A	ENSP00000359732.3	Q92581-1

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 787 AN: 112050 Hom.: 4 Cov.: 24

Gnomad AFR AF: 0.00120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00944

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00522

Gnomad FIN AF: 0.00313

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00665

GnomAD2 exomes AF: 0.00631 AC: 1124 AN: 178130 AF XY: 0.00647

Gnomad AFR exome AF: 0.000703

Gnomad AMR exome AF: 0.00265

Gnomad ASJ exome AF: 0.000135

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00404

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00704

GnomAD4 exome AF: 0.0110 AC: 11910 AN: 1085033 Hom.: 41 Cov.: 28 AF XY: 0.0108 AC XY: 3803 AN XY: 351625

African (AFR) AF: 0.00138 AC: 36 AN: 26175

American (AMR) AF: 0.00365 AC: 128 AN: 35088

Ashkenazi Jewish (ASJ) AF: 0.000156 AC: 3 AN: 19287

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30124

South Asian (SAS) AF: 0.00527 AC: 282 AN: 53484

European-Finnish (FIN) AF: 0.00435 AC: 176 AN: 40433

Middle Eastern (MID) AF: 0.00295 AC: 12 AN: 4070

European-Non Finnish (NFE) AF: 0.0130 AC: 10835 AN: 830729

Other (OTH) AF: 0.00957 AC: 437 AN: 45643

GnomAD4 genome AF: 0.00702 AC: 787 AN: 112106 Hom.: 4 Cov.: 24 AF XY: 0.00644 AC XY: 221 AN XY: 34300

African (AFR) AF: 0.00120 AC: 37 AN: 30878

American (AMR) AF: 0.00943 AC: 100 AN: 10600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00523 AC: 14 AN: 2675

European-Finnish (FIN) AF: 0.00313 AC: 19 AN: 6078

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.0114 AC: 606 AN: 53238

Other (OTH) AF: 0.00657 AC: 10 AN: 1523

Alfa AF: 0.00988 Hom.: 128

Bravo AF: 0.00712

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Christianson syndrome (3)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.027
DANN	Benign	0.61
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.016
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: rs188072063; hg19: chrX-135122231;