NM_001127898.4:c.164-2333T>G

Variant names:

• chrX-50067546-T-G
• rs41310663
• NM_001127898.4:c.164-2333T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127898.4(CLCN5):​c.164-2333T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000605 in 739,353 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 109 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., 17 hem., cov: 22)
  • Exomes 𝑓: 0.00061 (0 hom. 92 hem.)
• Consequence: CLCN5 NM_001127898.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0840
• 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: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant X-50067546-T-G is Benign according to our data. Variant chrX-50067546-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 369638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000593 (66/111310) while in subpopulation NFE AF = 0.000904 (48/53088). AF 95% confidence interval is 0.0007. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 17 XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	NM_001127898.4	MANE Select	c.164-2333T>G		intron	N/A	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.176-2333T>G		intron	N/A	NP_001427685.1
	CLCN5	NM_001440757.1		c.176-2333T>G		intron	N/A	NP_001427686.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.164-2333T>G		intron	N/A	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000376088.7	TSL:2	c.164-2333T>G		intron	N/A	ENSP00000365256.3	P51795-2
	CLCN5	ENST00000854414.1		c.164-2333T>G		intron	N/A	ENSP00000524473.1

Frequencies

GnomAD3 genomes AF: 0.000593 AC: 66 AN: 111257 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000770

Gnomad ASJ AF: 0.00227

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000382

Gnomad FIN AF: 0.000167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000904

Gnomad OTH AF: 0.000670

GnomAD4 exome AF: 0.000607 AC: 381 AN: 628043 Hom.: 0 Cov.: 11 AF XY: 0.000508 AC XY: 92 AN XY: 181181

African (AFR) AF: 0.0000821 AC: 1 AN: 12178

American (AMR) AF: 0.00 AC: 0 AN: 807

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 7 AN: 3895

East Asian (EAS) AF: 0.00 AC: 0 AN: 2980

South Asian (SAS) AF: 0.000256 AC: 3 AN: 11719

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 265

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1076

European-Non Finnish (NFE) AF: 0.000630 AC: 362 AN: 574380

Other (OTH) AF: 0.000386 AC: 8 AN: 20743

GnomAD4 genome AF: 0.000593 AC: 66 AN: 111310 Hom.: 0 Cov.: 22 AF XY: 0.000507 AC XY: 17 AN XY: 33514

African (AFR) AF: 0.0000326 AC: 1 AN: 30655

American (AMR) AF: 0.000769 AC: 8 AN: 10401

Ashkenazi Jewish (ASJ) AF: 0.00227 AC: 6 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3531

South Asian (SAS) AF: 0.000384 AC: 1 AN: 2607

European-Finnish (FIN) AF: 0.000167 AC: 1 AN: 5972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000904 AC: 48 AN: 53088

Other (OTH) AF: 0.000661 AC: 1 AN: 1512

Alfa AF: 0.00146 Hom.: 8

Bravo AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Dent disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.62
PhyloP100		-0.084
PromoterAI		0.13	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs41310663; hg19: chrX-49832201;