Genetic Variant NM_000083.3:c.1129C>G (chr7-143331615-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_000083.3(CLCN1):c.1129C>G(p.Arg377Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.76

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]

CLCN1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a helix (size 30) in uniprot entity CLCN1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000083.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3 link	c.1129C>G	p.Arg377Gly	missense_variant	Exon 10 of 23	ENST00000343257.7	NP_000074.3	P35523
CLCN1	NR_046453.2 link	n.1234C>G		non_coding_transcript_exon_variant	Exon 10 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLCN1	ENST00000343257.7 link	c.1129C>G	p.Arg377Gly	missense_variant	Exon 10 of 23	1	NM_000083.3	ENSP00000339867.2	P35523
CLCN1	ENST00000432192.6 link	n.*414C>G		non_coding_transcript_exon_variant	Exon 10 of 23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000432192.6 link	n.*414C>G		3_prime_UTR_variant	Exon 10 of 23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000650516.2 link	c.1129C>G	p.Arg377Gly	missense_variant	Exon 10 of 23			ENSP00000498052.2	A0A3B3IU72

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1129C>G (p.R377G) alteration is located in exon 10 (coding exon 10) of the CLCN1 gene. This alteration results from a C to G substitution at nucleotide position 1129, causing the arginine (R) at amino acid position 377 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jan 27, 2023

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is damaging. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.89

MutPred

0.67

Loss of MoRF binding (P = 0.0052);

MVP

0.99

MPC

0.84

ClinPred

1.0

GERP RS

5.1

Varity_R

0.92

gMVP

0.91

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over