7-143331315-GGG-CGT

Variant names:

• chr7-143331315-GGG-CGT
• NM_000083.3:c.1063_1064+1delGGGinsCGT
• CLCN1 p.Gly355Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP2

The NM_000083.3(CLCN1):​c.1063_1064+1delGGGinsCGT​(p.Gly355Arg) variant causes a splice donor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G355E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCN1 NM_000083.3 splice_donor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.99
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• myotonia congenita, autosomal recessive

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.6, offset of 28, new splice context is: gtgGTgagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 0.21191 (below the threshold of 3.09). Trascript score misZ: 0.95247 (below the threshold of 3.09). GenCC associations: The gene is linked to myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive, Thomsen and Becker disease.

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.1063_1064+1delGGGinsCGT	p.Gly355Arg	splice_donor missense splice_region intron	N/A	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.1168_1169+1delGGGinsCGT		splice_donor splice_region intron non_coding_transcript_exon	Exon 9 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.1063_1064+1delGGGinsCGT	p.Gly355Arg	splice_donor missense splice_region intron	N/A	ENSP00000339867.2	P35523
	CLCN1	ENST00000432192.6	TSL:1	n.*348_*349+1delGGGinsCGT		splice_region non_coding_transcript_exon	Exon 9 of 23	ENSP00000395949.2	H7C0N6
	CLCN1	ENST00000432192.6	TSL:1	n.*348_*349+1delGGGinsCGT		splice_donor 3_prime_UTR intron	Exon 9 of 23	ENSP00000395949.2	H7C0N6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-143028408;