chrX-10194980-C-G

Variant names:

• chrX-10194980-C-G
• rs1060502510
• NM_001830.4:c.314C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001830.4(CLCN4):​c.314C>G​(p.Ser105Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,209,721 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: CLCN4 NM_001830.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.14
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.314C>G	p.Ser105Cys	missense	Exon 5 of 13	NP_001821.2	P51793-1
	CLCN4	NM_001256944.2		c.32C>G	p.Ser11Cys	missense	Exon 3 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.314C>G	p.Ser105Cys	missense	Exon 5 of 13	ENSP00000370213.4	P51793-1
	CLCN4	ENST00000421085.7	TSL:5	c.314C>G	p.Ser105Cys	missense	Exon 4 of 13	ENSP00000405754.3	A0A7I2Y1J6
	CLCN4	ENST00000888019.1		c.314C>G	p.Ser105Cys	missense	Exon 5 of 13	ENSP00000558078.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111689 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098032 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363392

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000758 AC: 2 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54139

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841945

Other (OTH) AF: 0.00 AC: 0 AN: 46088

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111689 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33855

African (AFR) AF: 0.0000326 AC: 1 AN: 30695

American (AMR) AF: 0.00 AC: 0 AN: 10508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3553

South Asian (SAS) AF: 0.00 AC: 0 AN: 2678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53165

Other (OTH) AF: 0.00 AC: 0 AN: 1486

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.64	D
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.024	D
Polyphen		0.25	B
Vest4		0.55
MutPred		0.43		Gain of sheet (P = 0.0827)
MVP		1.0
MPC		1.4
ClinPred		0.88	D
GERP RS		3.4
Varity_R		0.43
gMVP		0.93
Mutation Taster		=71/29	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: rs1060502510; hg19: chrX-10163020;