chrX-50042407-C-T

Variant names:

• chrX-50042407-C-T
• rs111464924
• NM_001127898.4:c.108C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001127898.4(CLCN5):​c.108C>T​(p.Thr36Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,149,919 control chromosomes in the GnomAD database, including 1,027 homozygotes. There are 3,360 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (537 hom., 1819 hem., cov: 23)
  • Exomes 𝑓: 0.0062 (490 hom. 1541 hem.)
• Consequence: CLCN5 NM_001127898.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.294
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-50042407-C-T is Benign according to our data. Variant chrX-50042407-C-T is described in ClinVar as Benign. ClinVar VariationId is 1269710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.294 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

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.108C>T	p.Thr36Thr	synonymous	Exon 4 of 15	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.108C>T	p.Thr36Thr	synonymous	Exon 4 of 15	NP_001427685.1
	CLCN5	NM_001440757.1		c.108C>T	p.Thr36Thr	synonymous	Exon 4 of 15	NP_001427686.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.108C>T	p.Thr36Thr	synonymous	Exon 4 of 15	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000376088.7	TSL:2	c.108C>T	p.Thr36Thr	synonymous	Exon 4 of 15	ENSP00000365256.3	P51795-2
	CLCN5	ENST00000854414.1		c.108C>T	p.Thr36Thr	synonymous	Exon 4 of 13	ENSP00000524473.1

Frequencies

GnomAD3 genomes AF: 0.0606 AC: 6746 AN: 111332 Hom.: 537 Cov.: 23

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0332

GnomAD2 exomes AF: 0.0137 AC: 1561 AN: 114260 AF XY: 0.00481

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.00694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000819

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00548

GnomAD4 exome AF: 0.00618 AC: 6416 AN: 1038534 Hom.: 490 Cov.: 25 AF XY: 0.00471 AC XY: 1541 AN XY: 327154

African (AFR) AF: 0.214 AC: 5332 AN: 24865

American (AMR) AF: 0.00994 AC: 279 AN: 28062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18333

East Asian (EAS) AF: 0.00 AC: 0 AN: 27642

South Asian (SAS) AF: 0.000412 AC: 19 AN: 46133

European-Finnish (FIN) AF: 0.0000265 AC: 1 AN: 37784

Middle Eastern (MID) AF: 0.00746 AC: 30 AN: 4020

European-Non Finnish (NFE) AF: 0.000198 AC: 160 AN: 808020

Other (OTH) AF: 0.0136 AC: 595 AN: 43675

GnomAD4 genome AF: 0.0605 AC: 6743 AN: 111385 Hom.: 537 Cov.: 23 AF XY: 0.0540 AC XY: 1819 AN XY: 33669

African (AFR) AF: 0.212 AC: 6447 AN: 30454

American (AMR) AF: 0.0200 AC: 211 AN: 10557

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.000756 AC: 2 AN: 2645

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5994

Middle Eastern (MID) AF: 0.00465 AC: 1 AN: 215

European-Non Finnish (NFE) AF: 0.000603 AC: 32 AN: 53102

Other (OTH) AF: 0.0327 AC: 50 AN: 1527

Alfa AF: 0.0315 Hom.: 182

Bravo AF: 0.0686

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	2.9
DANN	Benign	0.60
PhyloP100		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs111464924; hg19: chrX-49807016;