rs770836890

Variant names:

• chr7-143345652-G-GTTC
• rs770836890
• NM_000083.3:c.2062_2063insTTC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_000083.3(CLCN1):​c.2062_2063insTTC​(p.Gly688delinsValArg) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000053 in 1,565,592 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: CLCN1 NM_000083.3 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 5.84

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 Uncertain_significance. Variant got 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000083.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.2062_2063insTTC	p.Gly688delinsValArg	disruptive_inframe_insertion	Exon 17 of 23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.2017_2018insTTC		non_coding_transcript_exon_variant	Exon 16 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.2062_2063insTTC	p.Gly688delinsValArg	disruptive_inframe_insertion	Exon 17 of 23	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*1347_*1348insTTC		non_coding_transcript_exon_variant	Exon 17 of 23	1		ENSP00000395949.2
CLCN1	ENST00000432192.6	n.*1347_*1348insTTC		3_prime_UTR_variant	Exon 17 of 23	1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.2062_2063insTTC	p.Gly688delinsValArg	disruptive_inframe_insertion	Exon 17 of 23			ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000146 AC: 25 AN: 170760 Hom.: 0 AF XY: 0.000131 AC XY: 12 AN XY: 91840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000380

Gnomad ASJ exome AF: 0.00267

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000144

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000502 AC: 71 AN: 1413386 Hom.: 0 Cov.: 33 AF XY: 0.0000458 AC XY: 32 AN XY: 698704

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.0000267

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000919

Gnomad4 OTH exome AF: 0.0000684

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.0000982

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Dec 22, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2062_2063insTTC variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC) data set, indicating it is not a benign variant in these populations. The c.2062_2063insTTC variant results in the replacement of a Glycine residue with a Valine residue, and the insertion of a single Arginine residue, denoted p.Gly688delinsValR. In-silico analysis predicts this variant does not affect gene splicing. -

not specified Uncertain:1

Jun 27, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Benign:1

Apr 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs770836890; hg19: chr7-143042745;