rs141271427

Variant names:

• chrX-10212463-C-T
• rs141271427
• NM_001830.4:c.1390-4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001830.4(CLCN4):​c.1390-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,207,928 control chromosomes in the GnomAD database, including 21 homozygotes. There are 508 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (11 hom., 239 hem., cov: 23)
  • Exomes 𝑓: 0.00095 (10 hom. 269 hem.)
• Consequence: CLCN4 NM_001830.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004745
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.18
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant X-10212463-C-T is Benign according to our data. Variant chrX-10212463-C-T is described in ClinVar as Benign. ClinVar VariationId is 415738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00829 (928/111875) while in subpopulation AFR AF = 0.0288 (885/30714). AF 95% confidence interval is 0.0272. There are 11 homozygotes in GnomAd4. There are 239 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN4	NM_001830.4	MANE Select	c.1390-4C>T		splice_region intron	N/A	NP_001821.2	P51793-1
	CLCN4	NM_001256944.2		c.1108-4C>T		splice_region 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.1390-4C>T		splice_region intron	N/A	ENSP00000370213.4	P51793-1
	CLCN4	ENST00000421085.7	TSL:5	c.1414-4C>T		splice_region intron	N/A	ENSP00000405754.3	A0A7I2Y1J6
	CLCN4	ENST00000888019.1		c.1390-4C>T		splice_region intron	N/A	ENSP00000558078.1

Frequencies

GnomAD3 genomes AF: 0.00828 AC: 926 AN: 111821 Hom.: 11 Cov.: 23

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00263

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: 0.0000941

Gnomad OTH AF: 0.00730

GnomAD2 exomes AF: 0.00247 AC: 447 AN: 181017 AF XY: 0.00147

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000994

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.000949 AC: 1040 AN: 1096053 Hom.: 10 Cov.: 30 AF XY: 0.000744 AC XY: 269 AN XY: 361523

African (AFR) AF: 0.0321 AC: 845 AN: 26364

American (AMR) AF: 0.00165 AC: 58 AN: 35135

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19300

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

South Asian (SAS) AF: 0.0000556 AC: 3 AN: 53965

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40479

Middle Eastern (MID) AF: 0.000969 AC: 4 AN: 4126

European-Non Finnish (NFE) AF: 0.0000309 AC: 26 AN: 840517

Other (OTH) AF: 0.00226 AC: 104 AN: 45990

GnomAD4 genome AF: 0.00829 AC: 928 AN: 111875 Hom.: 11 Cov.: 23 AF XY: 0.00702 AC XY: 239 AN XY: 34069

African (AFR) AF: 0.0288 AC: 885 AN: 30714

American (AMR) AF: 0.00254 AC: 27 AN: 10647

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000941 AC: 5 AN: 53107

Other (OTH) AF: 0.00721 AC: 11 AN: 1526

Alfa AF: 0.00488 Hom.: 26

Bravo AF: 0.0102

EpiCase AF: 0.00

EpiControl AF: 0.000239

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CLCN4-related disorder (1)
-	-	1	Intellectual disability, X-linked 49 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.7
DANN	Benign	0.89
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.14
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: rs141271427; hg19: chrX-10180503;