X-50042451-G-A

Position:

• chrX-50042451-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001127898.4(CLCN5):​c.152G>A​(p.Arg51Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000139 in 937,877 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000014 (0 hom. 4 hem.)
• Consequence: CLCN5 NM_001127898.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:4
• Conservation: PhyloP100: 5.70

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19400758).
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN5	NM_001127898.4	c.152G>A	p.Arg51Gln	missense_variant	4/15	ENST00000376091.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN5	ENST00000376091.8	c.152G>A	p.Arg51Gln	missense_variant	4/15	2	NM_001127898.4	P3
CLCN5	ENST00000376088.7	c.152G>A	p.Arg51Gln	missense_variant	4/15	2		P3
CLCN5	ENST00000482218.2	c.152G>A	p.Arg51Gln	missense_variant	3/3	3
CLCN5	ENST00000643129.1	c.116G>A	p.Arg39Gln	missense_variant, NMD_transcript_variant	1/14

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000127 AC: 1 AN: 79044 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 19710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000311

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 13 AN: 937877 Hom.: 0 Cov.: 18 AF XY: 0.0000151 AC XY: 4 AN XY: 265533

Gnomad4 AFR exome AF: 0.00

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: 0.0000148

Gnomad4 OTH exome AF: 0.0000506

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: no assertion criteria provided

Submissions by phenotype

Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CLCN5 p.Arg51Gln variant was not identified in the literature, nor was it identified in ClinVar, dbSNP or LOVD 3.0 databases. The variant was identified in control databases in 1 of 79044 chromosomes at a frequency of 0.00001265 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1 of 32137 chromosomes (freq: 0.000031), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg512 residue is not conserved in mammals and computational analyses (Align GVD, MutationTaster, SIFT, PolyPhen, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.Disease Information: Hemizygous pathogenic variants in males and homozygous or compound heterozygous pathogenic variants in females are associated with X-linked hypercalciuric nephrolithiasis, which comprises several related forms of hereditary renal tubular disorders caused by variants in the CLCN5 gene, including Dent disease (OMIM: 300009), X-linked recessive nephrolithiasis (OMIM: 310468), X-linked recessive hypophosphatemic rickets (OMIM: 300554), and low molecular weight proteinuria (OMIM: 308990). Dent disease is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, and at least one additional finding including nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, chronic kidney disease (CKD), and evidence of X-linked inheritance (GeneReviews, verbatim). Males younger than age ten years may manifest only LMW proteinuria and/or hypercalciuria, which are usually asymptomatic. (GeneReviews, verbatim) Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. (GeneReviews, verbatim) The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature. Disease severity can vary within the same family. (GeneReviews, verbatim) X-linked recessive hypophosphatemic rickets (OMIM: 300554) have been reported in an Italian family, in which fivemales presented with rickets or osteomalacia, hypophosphatemia, hypercalciuria, and proteinuria, and later developed nephrocalcinosis with progressive renal failure in adulthood (Bolino_1993_PMID:7915957). A French Family with X-linked recessive hypophosphatemic rickets has also been reported (Oudet_1997_PMID: 9187673).Familial Risk: X-linked hypercalciuric nephrolithiasis is inherited in an X-linked recessive manner. Each male offspring of an individual with a variant has a 50% chance of inheriting the variant and being affected. At conception, the female siblings of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers. -

X-linked recessive nephrolithiasis with renal failure Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CLCN5 p.Arg51Gln variant was not identified in the literature, nor was it identified in ClinVar, dbSNP or LOVD 3.0 databases. The variant was identified in control databases in 1 of 79044 chromosomes at a frequency of 0.00001265 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1 of 32137 chromosomes (freq: 0.000031), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg512 residue is not conserved in mammals and computational analyses (Align GVD, MutationTaster, SIFT, PolyPhen, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hypophosphatemic rickets, X-linked recessive Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CLCN5 p.Arg51Gln variant was not identified in the literature, nor was it identified in ClinVar, dbSNP or LOVD 3.0 databases. The variant was identified in control databases in 1 of 79044 chromosomes at a frequency of 0.00001265 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1 of 32137 chromosomes (freq: 0.000031), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg512 residue is not conserved in mammals and computational analyses (Align GVD, MutationTaster, SIFT, PolyPhen, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance -

Dent disease type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CLCN5 p.Arg51Gln variant was not identified in the literature, nor was it identified in ClinVar, dbSNP or LOVD 3.0 databases. The variant was identified in control databases in 1 of 79044 chromosomes at a frequency of 0.00001265 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1 of 32137 chromosomes (freq: 0.000031), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg512 residue is not conserved in mammals and computational analyses (Align GVD, MutationTaster, SIFT, PolyPhen, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	0.86	D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.070	N;N;.
REVEL	Uncertain	0.35
Sift	Benign	0.23	T;T;.
Sift4G	Benign	0.55	T;T;D
Polyphen		0.94	P;P;.
Vest4		0.21
MutPred		0.28		Loss of solvent accessibility (P = 0.0442);Loss of solvent accessibility (P = 0.0442);Loss of solvent accessibility (P = 0.0442);
MVP		0.74
MPC		0.78
ClinPred		0.53	D
GERP RS		3.4
gMVP		0.37

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1318459336; hg19: chrX-49807060; COSMIC: COSV65802630;