rs34904831

Variant names:

• chr7-143316192-C-G
• rs34904831
• NM_000083.3:c.-21C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-143316192-C-G
• chr7-143316192-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000083.3(CLCN1):​c.-21C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000674 in 148,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCN1 NM_000083.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• myotonia congenita, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• myotonia congenita, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Thomsen and Becker disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000083.3. 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
	CLCN1	NM_000083.3	MANE Select	c.-21C>G		5_prime_UTR	Exon 1 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.82C>G		non_coding_transcript_exon	Exon 1 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.-21C>G		5_prime_UTR	Exon 1 of 23	ENSP00000339867.2	P35523
	CLCN1	ENST00000650516.2		c.-21C>G		5_prime_UTR	Exon 1 of 23	ENSP00000498052.2	A0A3B3IU72
	CLCN1	ENST00000958857.1		c.-21C>G		upstream_gene	N/A	ENSP00000628916.1

Frequencies

GnomAD3 genomes AF: 0.00000674 AC: 1 AN: 148304 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449232 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721344

African (AFR) AF: 0.00 AC: 0 AN: 33320

American (AMR) AF: 0.00 AC: 0 AN: 44038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 85978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103960

Other (OTH) AF: 0.00 AC: 0 AN: 60026

GnomAD4 genome AF: 0.00000674 AC: 1 AN: 148304 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72246

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 39602

American (AMR) AF: 0.00 AC: 0 AN: 14588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.00 AC: 0 AN: 4666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67400

Other (OTH) AF: 0.00 AC: 0 AN: 2022

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 58

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.12
DANN	Benign	0.69
PhyloP100		-1.7
PromoterAI		-0.075	Neutral

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

Other links and lift over

dbSNP: rs34904831; hg19: chr7-143013285;