X-50042261-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001127898.4(CLCN5):​c.17-55G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 621,947 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000020 (0 hom. 0 hem.)
• Consequence: CLCN5 NM_001127898.4 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).

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>C		intron	N/A	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.17-55G>C		intron	N/A	NP_001427685.1
	CLCN5	NM_001440757.1		c.17-55G>C		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>C		intron	N/A	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000376088.7	TSL:2	c.17-55G>C		intron	N/A	ENSP00000365256.3	P51795-2
	CLCN5	ENST00000854414.1		c.17-55G>C		intron	N/A	ENSP00000524473.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111685 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000196 AC: 1 AN: 510262 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 123292

African (AFR) AF: 0.0000786 AC: 1 AN: 12728

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 33377

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2769

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 370669

Other (OTH) AF: 0.00 AC: 0 AN: 24406

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111685 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33871

African (AFR) AF: 0.0000326 AC: 1 AN: 30707

American (AMR) AF: 0.00 AC: 0 AN: 10543

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2646

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53118

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.10
DANN	Benign	0.37
PhyloP100		-0.58

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;