X-50086564-A-G

Variant names:

• chrX-50086564-A-G
• rs782591993
• NM_001127898.4:c.1251A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001127898.4(CLCN5):​c.1251A>G​(p.Arg417Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,208,758 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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 0.000027 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000017 (0 hom. 7 hem.)
• Consequence: CLCN5 NM_001127898.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.11
• Publications: 1 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant X-50086564-A-G is Benign according to our data. Variant chrX-50086564-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 368481.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.11 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	NM_001127898.4	MANE Select	c.1251A>G	p.Arg417Arg	synonymous	Exon 11 of 15	NP_001121370.1
	CLCN5	NM_001440756.1		c.1263A>G	p.Arg421Arg	synonymous	Exon 11 of 15	NP_001427685.1
	CLCN5	NM_001440757.1		c.1263A>G	p.Arg421Arg	synonymous	Exon 11 of 15	NP_001427686.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.1251A>G	p.Arg417Arg	synonymous	Exon 11 of 15	ENSP00000365259.3
	CLCN5	ENST00000307367.2	TSL:1	c.1041A>G	p.Arg347Arg	synonymous	Exon 8 of 12	ENSP00000304257.2
	CLCN5	ENST00000376108.7	TSL:1	c.1041A>G	p.Arg347Arg	synonymous	Exon 8 of 12	ENSP00000365276.3

Frequencies

GnomAD3 genomes AF: 0.0000271 AC: 3 AN: 110685 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183005 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000221

GnomAD4 exome AF: 0.0000173 AC: 19 AN: 1098073 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 7 AN XY: 363439

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54131

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000226 AC: 19 AN: 842015

Other (OTH) AF: 0.00 AC: 0 AN: 46091

GnomAD4 genome AF: 0.0000271 AC: 3 AN: 110685 Hom.: 0 Cov.: 22 AF XY: 0.0000304 AC XY: 1 AN XY: 32889

African (AFR) AF: 0.0000329 AC: 1 AN: 30381

American (AMR) AF: 0.00 AC: 0 AN: 10310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3516

South Asian (SAS) AF: 0.00 AC: 0 AN: 2591

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53012

Other (OTH) AF: 0.00 AC: 0 AN: 1490

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dent disease Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.7
DANN	Benign	0.65
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782591993; hg19: chrX-49851221;