X-50042451-G-T

Variant names:

• chrX-50042451-G-T
• rs1318459336
• NM_001127898.4:c.152G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127898.4(CLCN5):​c.152G>T​(p.Arg51Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000107 in 937,886 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R51Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000011 (0 hom. 0 hem.)
• Consequence: CLCN5 NM_001127898.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.70
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22884142).

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.152G>T	p.Arg51Leu	missense	Exon 4 of 15	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.152G>T	p.Arg51Leu	missense	Exon 4 of 15	NP_001427685.1
	CLCN5	NM_001440757.1		c.152G>T	p.Arg51Leu	missense	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.152G>T	p.Arg51Leu	missense	Exon 4 of 15	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000376088.7	TSL:2	c.152G>T	p.Arg51Leu	missense	Exon 4 of 15	ENSP00000365256.3	P51795-2
	CLCN5	ENST00000854414.1		c.152G>T	p.Arg51Leu	missense	Exon 4 of 13	ENSP00000524473.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000107 AC: 1 AN: 937886 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 265542

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

African (AFR) AF: 0.00 AC: 0 AN: 21520

American (AMR) AF: 0.00 AC: 0 AN: 21718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16294

East Asian (EAS) AF: 0.00 AC: 0 AN: 24680

South Asian (SAS) AF: 0.00 AC: 0 AN: 32234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3717

European-Non Finnish (NFE) AF: 0.00000135 AC: 1 AN: 742972

Other (OTH) AF: 0.00 AC: 0 AN: 39527

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.37	T
PhyloP100		5.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.18	N
REVEL	Uncertain	0.31
Sift	Benign	0.080	T
Sift4G	Benign	0.31	T
Polyphen		0.76	P
Vest4		0.33
MutPred		0.38		Loss of solvent accessibility (P = 0.0098)
MVP		0.64
MPC		0.81
ClinPred		0.67	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.52
Mutation Taster		=69/31	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1318459336; hg19: chrX-49807060;