ENST00000376108.7:c.-178C>T

Variant names:

• chrX-50067630-C-T
• rs781792158
• ENST00000376108.7:c.-178C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000376108.7(CLCN5):​c.-178C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 750,635 control chromosomes in the GnomAD database, including 1 homozygotes. There are 95 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 0.00021 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00043 (1 hom. 90 hem.)
• Consequence: CLCN5 ENST00000376108.7 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000215 (24/111850) while in subpopulation NFE AF = 0.000432 (23/53227). AF 95% confidence interval is 0.000295. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376108.7. 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.164-2249C>T		intron	N/A	NP_001121370.1	P51795-2
	CLCN5	NM_000084.5		c.-178C>T		5_prime_UTR	Exon 1 of 12	NP_000075.1	P51795-1
	CLCN5	NM_001440756.1		c.176-2249C>T		intron	N/A	NP_001427685.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	ENST00000376108.7	TSL:1	c.-178C>T		5_prime_UTR	Exon 1 of 12	ENSP00000365276.3	P51795-1
	CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.164-2249C>T		intron	N/A	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000376088.7	TSL:2	c.164-2249C>T		intron	N/A	ENSP00000365256.3	P51795-2

Frequencies

GnomAD3 genomes AF: 0.000215 AC: 24 AN: 111850 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000955

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: 0.000432

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000434 AC: 277 AN: 638785 Hom.: 1 Cov.: 19 AF XY: 0.000473 AC XY: 90 AN XY: 190425

African (AFR) AF: 0.0000808 AC: 1 AN: 12380

American (AMR) AF: 0.00 AC: 0 AN: 816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3957

East Asian (EAS) AF: 0.00 AC: 0 AN: 3013

South Asian (SAS) AF: 0.00 AC: 0 AN: 11964

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1101

European-Non Finnish (NFE) AF: 0.000450 AC: 263 AN: 584181

Other (OTH) AF: 0.000616 AC: 13 AN: 21110

GnomAD4 genome AF: 0.000215 AC: 24 AN: 111850 Hom.: 0 Cov.: 23 AF XY: 0.000147 AC XY: 5 AN XY: 34028

African (AFR) AF: 0.00 AC: 0 AN: 30773

American (AMR) AF: 0.0000955 AC: 1 AN: 10474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00 AC: 0 AN: 2658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6061

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000432 AC: 23 AN: 53227

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000162

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	-0.52
CADD	Benign	19
DANN	Benign	0.92
PhyloP100		1.5
PromoterAI		-0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Other links and lift over

dbSNP: rs781792158; hg19: chrX-49832285;