NM_001830.4:c.17C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001830.4(CLCN4):c.17C>T(p.Ala6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,205,521 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000038 ( 0 hom. 15 hem. )

Consequence

CLCN4
NM_001830.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.118

Publications

2 publications found

Variant links:

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)

CLCN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03835842).

BS2

High Hemizygotes in GnomAdExome4 at 15 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.17C>T	p.Ala6Val	missense	Exon 3 of 13	NP_001821.2	P51793-1
	CLCN4	NM_001256944.2		c.-38-9862C>T		intron	N/A	NP_001243873.1	P51793-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN4	ENST00000380833.9	TSL:1 MANE Select	c.17C>T	p.Ala6Val	missense	Exon 3 of 13	ENSP00000370213.4	P51793-1
CLCN4	ENST00000421085.7	TSL:5	c.17C>T	p.Ala6Val	missense	Exon 2 of 13	ENSP00000405754.3	A0A7I2Y1J6
CLCN4	ENST00000888019.1		c.17C>T	p.Ala6Val	missense	Exon 3 of 13	ENSP00000558078.1

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111488

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000668

AC:

AN:

179533

AF XY:

0.0000935

show subpopulations

Gnomad AFR exome

AF:

0.0000764

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000147

Gnomad FIN exome

AF:

0.000378

Gnomad NFE exome

AF:

0.0000249

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000384

AC:

AN:

1093979

Hom.:

Cov.:

AF XY:

0.0000417

AC XY:

AN XY:

359727

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26308

American (AMR)

AF:

0.00

AC:

AN:

34837

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19217

East Asian (EAS)

AF:

0.0000664

AC:

AN:

30134

South Asian (SAS)

AF:

0.0000373

AC:

AN:

53576

European-Finnish (FIN)

AF:

0.000346

AC:

AN:

40447

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4097

European-Non Finnish (NFE)

AF:

0.0000274

AC:

AN:

839478

Other (OTH)

AF:

0.00

AC:

AN:

45885

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000269

AC:

AN:

111542

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33750

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30648

American (AMR)

AF:

0.00

AC:

AN:

10499

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.000281

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2617

European-Finnish (FIN)

AF:

0.000166

AC:

AN:

6036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53122

Other (OTH)

AF:

0.00

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.78

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.72

M_CAP

Benign

0.066

MetaRNN

Benign

0.038

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.34

PhyloP100

0.12

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.3

REVEL

Benign

0.23

Sift

Benign

0.10

Sift4G

Uncertain

0.042

Polyphen

0.0010

Vest4

0.038

MVP

0.62

MPC

1.2

ClinPred

0.020

GERP RS

-3.7

Varity_R

0.056

gMVP

0.78

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over