chrX-50067749-C-T

Variant names:

• chrX-50067749-C-T
• rs782456542
• ENST00000376108.7:c.-59C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000084.5(CLCN5):​c.-59C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 750,345 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 47 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 4 hem., cov: 22)
  • Exomes 𝑓: 0.00023 (0 hom. 43 hem.)
• Consequence: CLCN5 NM_000084.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49
• 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000107 (12/111631) while in subpopulation AMR AF = 0.000286 (3/10480). AF 95% confidence interval is 0.0000775. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000084.5. 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.164-2130C>T		intron	N/A	NP_001121370.1	P51795-2
	CLCN5	NM_000084.5		c.-59C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_000075.1	P51795-1
	CLCN5	NM_000084.5		c.-59C>T		5_prime_UTR	Exon 1 of 12	NP_000075.1	P51795-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	ENST00000376108.7	TSL:1	c.-59C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000365276.3	P51795-1
	CLCN5	ENST00000376108.7	TSL:1	c.-59C>T		5_prime_UTR	Exon 1 of 12	ENSP00000365276.3	P51795-1
	CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.164-2130C>T		intron	N/A	ENSP00000365259.3	P51795-2

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 12 AN: 111631 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000286

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: 0.000151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000232 AC: 148 AN: 638714 Hom.: 0 Cov.: 17 AF XY: 0.000226 AC XY: 43 AN XY: 190336

African (AFR) AF: 0.00 AC: 0 AN: 12374

American (AMR) AF: 0.00 AC: 0 AN: 811

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3963

East Asian (EAS) AF: 0.00 AC: 0 AN: 3017

South Asian (SAS) AF: 0.00 AC: 0 AN: 11947

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 263

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1100

European-Non Finnish (NFE) AF: 0.000243 AC: 142 AN: 584128

Other (OTH) AF: 0.000284 AC: 6 AN: 21111

GnomAD4 genome AF: 0.000107 AC: 12 AN: 111631 Hom.: 0 Cov.: 22 AF XY: 0.000118 AC XY: 4 AN XY: 33817

African (AFR) AF: 0.0000326 AC: 1 AN: 30720

American (AMR) AF: 0.000286 AC: 3 AN: 10480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.00 AC: 0 AN: 2664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6013

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000151 AC: 8 AN: 53137

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.000253 Hom.: 1

Bravo AF: 0.000125

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dent disease type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.92
PhyloP100		2.5
PromoterAI		-0.023	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs782456542; hg19: chrX-49832404;