rs1554434400

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000083.3(CLCN1):​c.220C>A​(p.Gln74Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

CLCN1
NM_000083.3 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.169
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.046669662).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CLCN1NM_000083.3 linkuse as main transcriptc.220C>A p.Gln74Lys missense_variant 2/23 ENST00000343257.7 NP_000074.3 P35523
CLCN1NR_046453.2 linkuse as main transcriptn.322C>A non_coding_transcript_exon_variant 2/22

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLCN1ENST00000343257.7 linkuse as main transcriptc.220C>A p.Gln74Lys missense_variant 2/231 NM_000083.3 ENSP00000339867.2 P35523
CLCN1ENST00000650516.2 linkuse as main transcriptc.220C>A p.Gln74Lys missense_variant 2/23 ENSP00000498052.2 A0A3B3IU72
CLCN1ENST00000432192.6 linkuse as main transcriptn.-15C>A upstream_gene_variant 1 ENSP00000395949.2 H7C0N6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.060
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
0.064
DANN
Benign
0.38
DEOGEN2
Benign
0.089
.;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.021
N
LIST_S2
Benign
0.13
T;T
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.047
T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
0.34
.;N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.19
T
PROVEAN
Benign
-0.15
.;N
REVEL
Benign
0.17
Sift
Benign
0.78
.;T
Sift4G
Benign
1.0
.;T
Polyphen
0.0
.;B
Vest4
0.053
MutPred
0.26
Gain of ubiquitination at Q74 (P = 0.0014);Gain of ubiquitination at Q74 (P = 0.0014);
MVP
0.73
MPC
0.23
ClinPred
0.035
T
GERP RS
2.3
Varity_R
0.057
gMVP
0.30

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: rs1554434400; hg19: chr7-143016887; API