chr7-143316154-C-A

Position:

• chr7-143316154-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000083.3(CLCN1):​c.-59C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000797 in 1,254,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: CLCN1 NM_000083.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.224

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]

ACMG classification

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 (BayesDel_noAF=-0.57).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.-59C>A		5_prime_UTR_variant	1/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.44C>A		non_coding_transcript_exon_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.-59C>A		5_prime_UTR_variant	1/23	1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000650516.2	c.-59C>A		5_prime_UTR_variant	1/23			ENSP00000498052	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.97e-7 AC: 1 AN: 1254620 Hom.: 0 Cov.: 19 AF XY: 0.00000158 AC XY: 1 AN XY: 634030

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: 0.00000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

CLCN1: PM2, PM3:Supporting -

Congenital myotonia, autosomal recessive form Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Feb 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.5
DANN	Benign	0.85

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.

Other links and lift over

hg19: chr7-143013247;