CLCN4 p.Val275Leu

Variant names:

• chrX-10206756-G-T
• NM_001830.4:c.823G>T
• CLCN4 p.Val275Leu

Your query was ambiguous. Multiple possible variants found:

• chrX-10206756-G-T
• chrX-10206756-G-C
• chrX-10206756-GTG-TTA
• chrX-10206756-GTG-CTT
• chrX-10206756-GTG-CTC
• chrX-10206756-GTG-CTA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Moderate

The NM_001830.4(CLCN4):​c.823G>T​(p.Val275Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V275M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.55
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_001830.4 (CLCN4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_001830.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-10206756-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 209117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

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.823G>T	p.Val275Leu	missense	Exon 8 of 13	NP_001821.2	P51793-1
	CLCN4	NM_001256944.2		c.541G>T	p.Val181Leu	missense	Exon 6 of 11	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.823G>T	p.Val275Leu	missense	Exon 8 of 13	ENSP00000370213.4	P51793-1
	CLCN4	ENST00000421085.7	TSL:5	c.847G>T	p.Val283Leu	missense	Exon 8 of 13	ENSP00000405754.3	A0A7I2Y1J6
	CLCN4	ENST00000888019.1		c.823G>T	p.Val275Leu	missense	Exon 8 of 13	ENSP00000558078.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Varity_R		0.79
gMVP		0.99
Mutation Taster		=18/82	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-10174796;