NM_001127898.4:c.95A>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 9 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.95A>G	p.Asp32Gly	missense	Exon 4 of 15	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.95A>G	p.Asp32Gly	missense	Exon 4 of 15	NP_001427685.1
	CLCN5	NM_001440757.1		c.95A>G	p.Asp32Gly	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.95A>G	p.Asp32Gly	missense	Exon 4 of 15	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000376088.7	TSL:2	c.95A>G	p.Asp32Gly	missense	Exon 4 of 15	ENSP00000365256.3	P51795-2
	CLCN5	ENST00000854414.1		c.95A>G	p.Asp32Gly	missense	Exon 4 of 13	ENSP00000524473.1

Frequencies

GnomAD3 genomes AF: 0.000340 AC: 38 AN: 111825 Hom.: 1 Cov.: 22

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

GnomAD2 exomes AF: 0.000563 AC: 68 AN: 120844 AF XY: 0.000635

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 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

African (AFR) AF: 0.0000790 AC: 2 AN: 25305

American (AMR) AF: 0.0000343 AC: 1 AN: 29145

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 200 AN: 18496

East Asian (EAS) AF: 0.00 AC: 0 AN: 28210

South Asian (SAS) AF: 0.00 AC: 0 AN: 47542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38175

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4049

European-Non Finnish (NFE) AF: 0.0000356 AC: 29 AN: 815040

Other (OTH) AF: 0.000702 AC: 31 AN: 44159

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

African (AFR) AF: 0.0000326 AC: 1 AN: 30697

American (AMR) AF: 0.00 AC: 0 AN: 10554

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 29 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3585

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000150 AC: 8 AN: 53163

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.000614 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

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CLCN5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.0082	T
MetaSVM	Uncertain	0.046	D
PhyloP100		7.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.092	T
Polyphen		0.45	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
Mutation Taster		=61/39	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs202230774; hg19: chrX-49807003;