X-50042394-A-G

Variant names:

• chrX-50042394-A-G
• rs202230774
• NM_001127898.4:c.95A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001127898.4(CLCN5):​c.95A>G​(p.Asp32Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000259 in 1,161,946 control chromosomes in the GnomAD database, including 1 homozygotes. There are 99 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., 9 hem., cov: 22)
  • Exomes 𝑓: 0.00025 (0 hom. 90 hem.)
• Consequence: CLCN5 NM_001127898.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.03

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008176386).
• BP6: Variant X-50042394-A-G is Benign according to our data. Variant chrX-50042394-A-G is described in ClinVar as [Benign]. Clinvar id is 3048658.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00034 (38/111825) while in subpopulation NFE AF= 0.00015 (8/53163). AF 95% confidence interval is 0.0000745. There are 1 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN5	NM_001127898.4	c.95A>G	p.Asp32Gly	missense_variant	Exon 4 of 15	ENST00000376091.8	NP_001121370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN5	ENST00000376091.8	c.95A>G	p.Asp32Gly	missense_variant	Exon 4 of 15	2	NM_001127898.4	ENSP00000365259.3
CLCN5	ENST00000376088.7	c.95A>G	p.Asp32Gly	missense_variant	Exon 4 of 15	2		ENSP00000365256.3
CLCN5	ENST00000482218.2	c.95A>G	p.Asp32Gly	missense_variant	Exon 3 of 3	3		ENSP00000476732.1
CLCN5	ENST00000643129.1	n.56A>G		non_coding_transcript_exon_variant	Exon 1 of 14			ENSP00000496056.1

Frequencies

GnomAD3 genomes AF: 0.000340 AC: 38 AN: 111825 Hom.: 1 Cov.: 22 AF XY: 0.000265 AC XY: 9 AN XY: 34007

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000563 AC: 68 AN: 120844 Hom.: 0 AF XY: 0.000635 AC XY: 22 AN XY: 34666

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00928

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000609

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.000250 AC: 263 AN: 1050121 Hom.: 0 Cov.: 26 AF XY: 0.000270 AC XY: 90 AN XY: 333839

Gnomad4 AFR exome AF: 0.0000790

Gnomad4 AMR exome AF: 0.0000343

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000356

Gnomad4 OTH exome AF: 0.000702

GnomAD4 genome AF: 0.000340 AC: 38 AN: 111825 Hom.: 1 Cov.: 22 AF XY: 0.000265 AC XY: 9 AN XY: 34007

Gnomad4 AFR AF: 0.0000326

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000150

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000583 Hom.: 25

Bravo AF: 0.000374

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000728 AC: 4

ExAC AF: 0.000409 AC: 46

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CLCN5-related disorder Benign:1

Dec 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	.;T;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.0082	T;T;T
MetaSVM	Uncertain	0.046	D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N;N;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;D;.
Sift4G	Benign	0.092	T;T;T
Polyphen		0.45	B;B;.
Vest4		0.27
MVP		0.80
MPC		1.2
ClinPred		0.087	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.39

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs202230774; hg19: chrX-49807003;