X-10185070-TGATGGATTTCCTC-T

Variant names:

• chrX-10185070-TGATGGATTTCCTC-T
• rs1923775114
• NM_001830.4:c.43_55delGATTTCCTCGATG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001830.4(CLCN4):​c.43_55delGATTTCCTCGATG​(p.Asp15SerfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CLCN4 NM_001830.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.80
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 63 pathogenic variants in the truncated region.
• PP5: Variant X-10185070-TGATGGATTTCCTC-T is Pathogenic according to our data. Variant chrX-10185070-TGATGGATTTCCTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 253112.Status of the report is no_assertion_criteria_provided, 0 stars.

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.43_55delGATTTCCTCGATG	p.Asp15SerfsTer18	frameshift	Exon 3 of 13	NP_001821.2	P51793-1
	CLCN4	NM_001256944.2		c.-38-9836_-38-9824delGATTTCCTCGATG		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.43_55delGATTTCCTCGATG	p.Asp15SerfsTer18	frameshift	Exon 3 of 13	ENSP00000370213.4	P51793-1
	CLCN4	ENST00000421085.7	TSL:5	c.43_55delGATTTCCTCGATG	p.Asp15SerfsTer18	frameshift	Exon 2 of 13	ENSP00000405754.3	A0A7I2Y1J6
	CLCN4	ENST00000888019.1		c.43_55delGATTTCCTCGATG	p.Asp15SerfsTer18	frameshift	Exon 3 of 13	ENSP00000558078.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, X-linked 49 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1923775114; hg19: chrX-10153110;