rs777452988

Variant names:

• chrX-10206507-C-G
• rs777452988
• NM_001830.4:c.705C>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001830.4(CLCN4):​c.705C>G​(p.Gly235Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,208,945 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 4 hem.)
• Consequence: CLCN4 NM_001830.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.307
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant X-10206507-C-G is Benign according to our data. Variant chrX-10206507-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 210735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.307 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	NM_001830.4	MANE Select	c.705C>G	p.Gly235Gly	synonymous	Exon 7 of 13	NP_001821.2
	CLCN4	NM_001256944.2		c.423C>G	p.Gly141Gly	synonymous	Exon 5 of 11	NP_001243873.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	ENST00000380833.9	TSL:1 MANE Select	c.705C>G	p.Gly235Gly	synonymous	Exon 7 of 13	ENSP00000370213.4
	CLCN4	ENST00000421085.7	TSL:5	c.729C>G	p.Gly243Gly	synonymous	Exon 7 of 13	ENSP00000405754.3
	CLCN4	ENST00000380829.5	TSL:5	c.705C>G	p.Gly235Gly	synonymous	Exon 6 of 13	ENSP00000370209.1

Frequencies

GnomAD3 genomes AF: 0.0000445 AC: 5 AN: 112444 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000169 AC: 3 AN: 177352 AF XY: 0.0000321

Gnomad AFR exome AF: 0.0000782

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000254

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 9 AN: 1096501 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 4 AN XY: 361929

African (AFR) AF: 0.00 AC: 0 AN: 26391

American (AMR) AF: 0.00 AC: 0 AN: 35023

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19360

East Asian (EAS) AF: 0.00 AC: 0 AN: 30177

South Asian (SAS) AF: 0.00 AC: 0 AN: 53727

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4107

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 841284

Other (OTH) AF: 0.00 AC: 0 AN: 46032

GnomAD4 genome AF: 0.0000445 AC: 5 AN: 112444 Hom.: 0 Cov.: 23 AF XY: 0.0000289 AC XY: 1 AN XY: 34584

African (AFR) AF: 0.0000969 AC: 3 AN: 30957

American (AMR) AF: 0.00 AC: 0 AN: 10619

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.00 AC: 0 AN: 2725

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6143

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53321

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000264

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CLCN4-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Benign	0.76
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism

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: rs777452988; hg19: chrX-10174547;