chrX-50067761-G-T

Position:

chrX-50067761-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PVS1_ModeratePP3BS1_SupportingBS2

The ENST00000376108.7(CLCN5):c.-48+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.000131 in 747,085 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.00015 ( 0 hom. 25 hem. )

Consequence

CLCN5
ENST00000376108.7 splice_donor

Scores

Splicing: ADA: 0.8039

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.32

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0821062 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.1, offset of -45, new splice context is: aagGTtatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00015 (95/635347) while in subpopulation NFE AF= 0.000158 (92/581029). AF 95% confidence interval is 0.000131. There are 0 homozygotes in gnomad4_exome. There are 25 alleles in male gnomad4_exome subpopulation. Median coverage is 15. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 25 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN5	NM_001127898.4 linkuse as main transcript	c.164-2118G>T		intron_variant		ENST00000376091.8

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
CLCN5	ENST00000376108.7 linkuse as main transcript	c.-48+1G>T	splice_donor_variant	1		A1	P51795-1
CLCN5	ENST00000376091.8 linkuse as main transcript	c.164-2118G>T	intron_variant	2	NM_001127898.4	P3	P51795-2
CLCN5	ENST00000376088.7 linkuse as main transcript	c.164-2118G>T	intron_variant	2		P3	P51795-2
CLCN5	ENST00000643129.1 linkuse as main transcript	c.*261-2118G>T	intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111738

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33904

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000376

Gnomad OTH

AF:

0.000668

GnomAD4 exome

AF:

0.000150

AC:

AN:

635347

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

187041

show subpopulations

Gnomad4 AFR exome

AF:

0.0000813

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000158

Gnomad4 OTH exome

AF:

0.0000951

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111738

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33904

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.000668

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 28, 2023

- -

Dent disease type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 11, 2018

This variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.80

dbscSNV1_RF

Pathogenic

0.74

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.96

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over