X-10185033-A-G

Variant names:

• chrX-10185033-A-G
• rs1555973635
• NM_001830.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001830.4(CLCN4):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000922 in 1,085,185 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: CLCN4 NM_001830.4 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 2.56
• Publications: 0 publications found

Genes affected

CLCN4 (HGNC:2022): (chloride voltage-gated channel 4) The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. Chloride channel 4 has an evolutionary conserved CpG island and is conserved in both mouse and hamster. This gene is mapped in close proximity to APXL (Apical protein Xenopus laevis-like) and OA1 (Ocular albinism type I), which are both located on the human X chromosome at band p22.3. The physiological role of chloride channel 4 remains unknown but may contribute to the pathogenesis of neuronal disorders. Alternate splicing results in two transcript variants that encode different proteins. [provided by RefSeq, Mar 2012]

CLCN4 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, X-linked 49

  Inheritance: XL Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 7 codons. Genomic position: 10185051. Lost 0.008 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-10185033-A-G is Pathogenic according to our data. Variant chrX-10185033-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 489100.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001830.4. 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
	CLCN4	NM_001830.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 3 of 13	NP_001821.2	P51793-1
	CLCN4	NM_001256944.2		c.-38-9878A>G		intron	N/A	NP_001243873.1	P51793-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	ENST00000380833.9	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 3 of 13	ENSP00000370213.4	P51793-1
	CLCN4	ENST00000421085.7	TSL:5	c.1A>G	p.Met1?	start_lost	Exon 2 of 13	ENSP00000405754.3	A0A7I2Y1J6
	CLCN4	ENST00000888019.1		c.1A>G	p.Met1?	start_lost	Exon 3 of 13	ENSP00000558078.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1085185 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 352693

African (AFR) AF: 0.00 AC: 0 AN: 26102

American (AMR) AF: 0.00 AC: 0 AN: 34138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18941

East Asian (EAS) AF: 0.00 AC: 0 AN: 29942

South Asian (SAS) AF: 0.00 AC: 0 AN: 52511

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40309

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4039

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 833755

Other (OTH) AF: 0.00 AC: 0 AN: 45448

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, X-linked 49 (1)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.13	T
PhyloP100		2.6
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.34
Sift	Benign	0.083	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.48
MutPred		0.99		Loss of solvent accessibility (P = 0.3103)
MVP		0.93
ClinPred		0.95	D
GERP RS		3.9
Varity_R		0.29
gMVP		0.92
Mutation Taster		=10/190	disease causing (ClinVar)

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: rs1555973635; hg19: chrX-10153073;