Genetic Variant CLCN5:p.Val798GlyfsTer6 (chrX-50092156-GGATGTGTTAAAGCATATAGCACA-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_ModeratePP5

The NM_001127898.4(CLCN5):c.2393_2415delTGTTAAAGCATATAGCACAGATG(p.Val798GlyfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 23)

Consequence

CLCN5
NM_001127898.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.85

Publications

0 publications found

Variant links:

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

CLCN5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0237 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PP5

Variant X-50092156-GGATGTGTTAAAGCATATAGCACA-G is Pathogenic according to our data. Variant chrX-50092156-GGATGTGTTAAAGCATATAGCACA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 208002.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN5	NM_001127898.4	MANE Select	c.2393_2415delTGTTAAAGCATATAGCACAGATG	p.Val798GlyfsTer6	frameshift	Exon 15 of 15	NP_001121370.1	P51795-2
CLCN5	NM_001440756.1		c.2405_2427delTGTTAAAGCATATAGCACAGATG	p.Val802GlyfsTer6	frameshift	Exon 15 of 15	NP_001427685.1
CLCN5	NM_001440757.1		c.2405_2427delTGTTAAAGCATATAGCACAGATG	p.Val802GlyfsTer6	frameshift	Exon 15 of 15	NP_001427686.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.2393_2415delTGTTAAAGCATATAGCACAGATG	p.Val798GlyfsTer6	frameshift	Exon 15 of 15	ENSP00000365259.3	P51795-2
CLCN5	ENST00000307367.2	TSL:1	c.2183_2205delTGTTAAAGCATATAGCACAGATG	p.Val728GlyfsTer6	frameshift	Exon 12 of 12	ENSP00000304257.2	P51795-1
CLCN5	ENST00000376108.7	TSL:1	c.2183_2205delTGTTAAAGCATATAGCACAGATG	p.Val728GlyfsTer6	frameshift	Exon 12 of 12	ENSP00000365276.3	P51795-1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dent disease type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.9

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over