chrX-50042305-T-G

Variant names:

• chrX-50042305-T-G
• NM_001127898.4:c.17-11T>G

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.17-11T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CLCN5 NM_001127898.4 intron
• Scores: Splicing: ADA: 0.01269
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.371
• 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: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

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=-0.58).

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.17-11T>G		intron	N/A	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.17-11T>G		intron	N/A	NP_001427685.1
	CLCN5	NM_001440757.1		c.17-11T>G		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.17-11T>G		intron	N/A	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000376088.7	TSL:2	c.17-11T>G		intron	N/A	ENSP00000365256.3	P51795-2
	CLCN5	ENST00000854414.1		c.17-11T>G		intron	N/A	ENSP00000524473.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.87
PhyloP100		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.18

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

Other links and lift over

hg19: chrX-49806914;