X-50042261-G-A

Variant names:

• chrX-50042261-G-A
• rs183862468
• NM_001127898.4:c.17-55G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001127898.4(CLCN5):​c.17-55G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 621,999 control chromosomes in the GnomAD database, including 2 homozygotes. There are 143 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 0.0035 (1 hom., 99 hem., cov: 23)
  • Exomes 𝑓: 0.00047 (1 hom. 44 hem.)
• Consequence: CLCN5 NM_001127898.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.580
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant X-50042261-G-A is Benign according to our data. Variant chrX-50042261-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1215662.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00346 (387/111741) while in subpopulation AFR AF = 0.0122 (374/30777). AF 95% confidence interval is 0.0111. There are 1 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 99 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127898.4. 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.17-55G>A		intron	N/A	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.17-55G>A		intron	N/A	NP_001427685.1
	CLCN5	NM_001440757.1		c.17-55G>A		intron	N/A	NP_001427686.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.17-55G>A		intron	N/A	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000376088.7	TSL:2	c.17-55G>A		intron	N/A	ENSP00000365256.3	P51795-2
	CLCN5	ENST00000854414.1		c.17-55G>A		intron	N/A	ENSP00000524473.1

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 387 AN: 111685 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000854

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: 0.0000377

Gnomad OTH AF: 0.00133

GnomAD4 exome AF: 0.000470 AC: 240 AN: 510258 Hom.: 1 AF XY: 0.000357 AC XY: 44 AN XY: 123290

African (AFR) AF: 0.0156 AC: 199 AN: 12725

American (AMR) AF: 0.000258 AC: 4 AN: 15492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11173

East Asian (EAS) AF: 0.00 AC: 0 AN: 22324

South Asian (SAS) AF: 0.00 AC: 0 AN: 17324

European-Finnish (FIN) AF: 0.0000300 AC: 1 AN: 33377

Middle Eastern (MID) AF: 0.000361 AC: 1 AN: 2769

European-Non Finnish (NFE) AF: 0.0000162 AC: 6 AN: 370669

Other (OTH) AF: 0.00119 AC: 29 AN: 24405

GnomAD4 genome AF: 0.00346 AC: 387 AN: 111741 Hom.: 1 Cov.: 23 AF XY: 0.00292 AC XY: 99 AN XY: 33937

African (AFR) AF: 0.0122 AC: 374 AN: 30777

American (AMR) AF: 0.000853 AC: 9 AN: 10556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53111

Other (OTH) AF: 0.00132 AC: 2 AN: 1520

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00427

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.12
DANN	Benign	0.44
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs183862468; hg19: chrX-49806870;