rs781805006

Variant names:

• chrX-50067578-G-A
• rs781805006
• ENST00000376108.7:c.-230G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000376108.7(CLCN5):​c.-230G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000797 in 751,643 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 189 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., 20 hem., cov: 23)
  • Exomes 𝑓: 0.00082 (0 hom. 169 hem.)
• Consequence: CLCN5 ENST00000376108.7 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.34
• Publications: 0 publications found

Genes affected

CLCN5 (HGNC:2023): (chloride voltage-gated channel 5) This gene encodes a member of the ClC family of chloride ion channels and ion transporters. The encoded protein is primarily localized to endosomal membranes and may function to facilitate albumin uptake by the renal proximal tubule. Mutations in this gene have been found in Dent disease and renal tubular disorders complicated by nephrolithiasis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

CLCN5 Gene-Disease associations (from GenCC):

• Dent disease type 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant X-50067578-G-A is Benign according to our data. Variant chrX-50067578-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 368470.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000644 (72/111744) while in subpopulation AMR AF = 0.00258 (27/10485). AF 95% confidence interval is 0.00182. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 20 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376108.7. 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
	CLCN5	NM_001127898.4	MANE Select	c.164-2301G>A		intron	N/A	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.176-2301G>A		intron	N/A	NP_001427685.1
	CLCN5	NM_001440757.1		c.176-2301G>A		intron	N/A	NP_001427686.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	ENST00000376108.7	TSL:1	c.-230G>A		5_prime_UTR	Exon 1 of 12	ENSP00000365276.3	P51795-1
	CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.164-2301G>A		intron	N/A	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000376088.7	TSL:2	c.164-2301G>A		intron	N/A	ENSP00000365256.3	P51795-2

Frequencies

GnomAD3 genomes AF: 0.000645 AC: 72 AN: 111691 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00258

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.000677

Gnomad OTH AF: 0.00201

GnomAD4 exome AF: 0.000824 AC: 527 AN: 639899 Hom.: 0 Cov.: 18 AF XY: 0.000882 AC XY: 169 AN XY: 191517

African (AFR) AF: 0.000403 AC: 5 AN: 12398

American (AMR) AF: 0.00 AC: 0 AN: 815

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3971

East Asian (EAS) AF: 0.00 AC: 0 AN: 3018

South Asian (SAS) AF: 0.00 AC: 0 AN: 11985

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 263

Middle Eastern (MID) AF: 0.00363 AC: 4 AN: 1102

European-Non Finnish (NFE) AF: 0.000868 AC: 508 AN: 585203

Other (OTH) AF: 0.000473 AC: 10 AN: 21144

GnomAD4 genome AF: 0.000644 AC: 72 AN: 111744 Hom.: 0 Cov.: 23 AF XY: 0.000589 AC XY: 20 AN XY: 33954

African (AFR) AF: 0.0000325 AC: 1 AN: 30808

American (AMR) AF: 0.00258 AC: 27 AN: 10485

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6043

Middle Eastern (MID) AF: 0.0230 AC: 5 AN: 217

European-Non Finnish (NFE) AF: 0.000677 AC: 36 AN: 53152

Other (OTH) AF: 0.00198 AC: 3 AN: 1513

Alfa AF: 0.000498 Hom.: 1

Bravo AF: 0.00111

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Dent disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.94
PhyloP100		2.3
PromoterAI		0.19	Neutral

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: rs781805006; hg19: chrX-49832233;