Genetic Variant CLCN5:p.Gly330Asp (chrX-50086035-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_001127898.4(CLCN5):c.989G>A(p.Gly330Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,091,267 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G330V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

CLCN5
NM_001127898.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.89

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: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001127898.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-50086035-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11808.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

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.989G>A	p.Gly330Asp	missense	Exon 10 of 15	NP_001121370.1	P51795-2
CLCN5	NM_001440756.1		c.1001G>A	p.Gly334Asp	missense	Exon 10 of 15	NP_001427685.1
CLCN5	NM_001440757.1		c.1001G>A	p.Gly334Asp	missense	Exon 10 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.989G>A	p.Gly330Asp	missense	Exon 10 of 15	ENSP00000365259.3	P51795-2
CLCN5	ENST00000307367.2	TSL:1	c.779G>A	p.Gly260Asp	missense	Exon 7 of 12	ENSP00000304257.2	P51795-1
CLCN5	ENST00000376108.7	TSL:1	c.779G>A	p.Gly260Asp	missense	Exon 7 of 12	ENSP00000365276.3	P51795-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.16e-7

AC:

AN:

1091267

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

356781

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26264

American (AMR)

AF:

0.00

AC:

AN:

35195

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19337

East Asian (EAS)

AF:

0.00

AC:

AN:

30194

South Asian (SAS)

AF:

0.00

AC:

AN:

53984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40481

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

835813

Other (OTH)

AF:

0.00

AC:

AN:

45886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.69

BayesDel_noAF

Pathogenic

0.76

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

PhyloP100

9.9

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.96

MutPred

0.88

Loss of catalytic residue at G261 (P = 0.1204)

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

6.0

Varity_R

0.99

gMVP

0.99

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over