NM_001127898.4:c.299G>A

Variant names:

• chrX-50070014-G-A
• rs782470964
• NM_001127898.4:c.299G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_001127898.4(CLCN5):​c.299G>A​(p.Arg100Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000912 in 1,206,775 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R100W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: CLCN5 NM_001127898.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.63
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33382487).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000453 (5/110441) while in subpopulation AFR AF = 0.000165 (5/30378). AF 95% confidence interval is 0.0000643. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 23. 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 2 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.299G>A	p.Arg100Gln	missense	Exon 5 of 15	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.311G>A	p.Arg104Gln	missense	Exon 5 of 15	NP_001427685.1
	CLCN5	NM_001440757.1		c.311G>A	p.Arg104Gln	missense	Exon 5 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.299G>A	p.Arg100Gln	missense	Exon 5 of 15	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000307367.2	TSL:1	c.89G>A	p.Arg30Gln	missense	Exon 2 of 12	ENSP00000304257.2	P51795-1
	CLCN5	ENST00000376108.7	TSL:1	c.89G>A	p.Arg30Gln	missense	Exon 2 of 12	ENSP00000365276.3	P51795-1

Frequencies

GnomAD3 genomes AF: 0.0000453 AC: 5 AN: 110441 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000165 AC: 3 AN: 181749 AF XY: 0.00

Gnomad AFR exome AF: 0.0000765

Gnomad AMR exome AF: 0.0000734

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1096334 Hom.: 0 Cov.: 29 AF XY: 0.00000553 AC XY: 2 AN XY: 361984

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000379 AC: 1 AN: 26355

American (AMR) AF: 0.0000855 AC: 3 AN: 35094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19334

East Asian (EAS) AF: 0.00 AC: 0 AN: 30175

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53935

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840904

Other (OTH) AF: 0.00 AC: 0 AN: 46003

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00117289), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000453 AC: 5 AN: 110441 Hom.: 0 Cov.: 23 AF XY: 0.0000612 AC XY: 2 AN XY: 32693

African (AFR) AF: 0.000165 AC: 5 AN: 30378

American (AMR) AF: 0.00 AC: 0 AN: 10411

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2628

East Asian (EAS) AF: 0.00 AC: 0 AN: 3519

South Asian (SAS) AF: 0.00 AC: 0 AN: 2433

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52756

Other (OTH) AF: 0.00 AC: 0 AN: 1469

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	X-linked recessive nephrolithiasis with renal failure;C1839874:Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis;C1845168:Hypophosphatemic rickets, X-linked recessive;C1848336:Dent disease type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.6	L
PhyloP100		5.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.62
Sift	Benign	0.061	T
Sift4G	Benign	0.076	T
Polyphen		1.0	D
Vest4		0.36
MutPred		0.48		Loss of MoRF binding (P = 0.043)
MVP		0.92
MPC		0.79
ClinPred		0.31	T
GERP RS		5.5
Varity_R		0.70
gMVP		0.97
Mutation Taster		=30/70	disease causing

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: rs782470964; hg19: chrX-49834669;