rs111482384

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000343257.7(CLCN1):ā€‹c.461A>Gā€‹(p.Gln154Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,614,212 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q154H) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0097 ( 33 hom., cov: 32)
Exomes š‘“: 0.0011 ( 24 hom. )

Consequence

CLCN1
ENST00000343257.7 missense

Scores

1
17

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.55
Variant links:
Genes affected
CLCN1 (HGNC:2019): (chloride voltage-gated channel 1) 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. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0039210916).
BP6
Variant 7-143321392-A-G is Benign according to our data. Variant chr7-143321392-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 359101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143321392-A-G is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0097 (1478/152322) while in subpopulation AFR AF= 0.033 (1373/41568). AF 95% confidence interval is 0.0316. There are 33 homozygotes in gnomad4. There are 681 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 33 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CLCN1NM_000083.3 linkuse as main transcriptc.461A>G p.Gln154Arg missense_variant 4/23 ENST00000343257.7 NP_000074.3
CLCN1NR_046453.2 linkuse as main transcriptn.563A>G non_coding_transcript_exon_variant 4/22

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLCN1ENST00000343257.7 linkuse as main transcriptc.461A>G p.Gln154Arg missense_variant 4/231 NM_000083.3 ENSP00000339867 P4
CLCN1ENST00000432192.6 linkuse as main transcriptc.230A>G p.Gln77Arg missense_variant, NMD_transcript_variant 3/231 ENSP00000395949
CLCN1ENST00000650516.2 linkuse as main transcriptc.461A>G p.Gln154Arg missense_variant 4/23 ENSP00000498052 A2

Frequencies

GnomAD3 genomes
AF:
0.00961
AC:
1462
AN:
152204
Hom.:
33
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0328
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00471
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.0110
GnomAD3 exomes
AF:
0.00256
AC:
644
AN:
251428
Hom.:
10
AF XY:
0.00180
AC XY:
245
AN XY:
135892
show subpopulations
Gnomad AFR exome
AF:
0.0325
Gnomad AMR exome
AF:
0.00228
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000967
Gnomad OTH exome
AF:
0.00261
GnomAD4 exome
AF:
0.00107
AC:
1565
AN:
1461890
Hom.:
24
Cov.:
33
AF XY:
0.000897
AC XY:
652
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0358
Gnomad4 AMR exome
AF:
0.00241
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000359
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000656
Gnomad4 OTH exome
AF:
0.00233
GnomAD4 genome
AF:
0.00970
AC:
1478
AN:
152322
Hom.:
33
Cov.:
32
AF XY:
0.00914
AC XY:
681
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0330
Gnomad4 AMR
AF:
0.00470
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.0109
Alfa
AF:
0.00216
Hom.:
9
Bravo
AF:
0.0110
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.0345
AC:
152
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00313
AC:
380
Asia WGS
AF:
0.00289
AC:
10
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2023CLCN1: BP4, BS2 -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxNov 10, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Batten-Turner congenital myopathy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
5.3
DANN
Benign
0.33
DEOGEN2
Benign
0.097
.;T
Eigen
Benign
-0.93
Eigen_PC
Benign
-0.78
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.10
T;T
MetaRNN
Benign
0.0039
T;T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
0.81
.;L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.49
.;N
REVEL
Benign
0.23
Sift
Benign
0.52
.;T
Sift4G
Benign
0.52
.;T
Polyphen
0.0
.;B
Vest4
0.14
MVP
0.80
MPC
0.20
ClinPred
0.0016
T
GERP RS
2.6
Varity_R
0.077
gMVP
0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs111482384; hg19: chr7-143018485; API