rs940864

Variant names:

• chr7-143342218-A-G
• rs940864
• NM_000083.3:c.1796+76A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-143342218-A-G
• chr7-143342218-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000083.3(CLCN1):​c.1796+76A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,515,792 control chromosomes in the GnomAD database, including 133,522 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15213 hom., cov: 32)
  • Exomes 𝑓: 0.41 (118309 hom.)
• Consequence: CLCN1 NM_000083.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0860
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-143342218-A-G is Benign according to our data. Variant chr7-143342218-A-G is described in ClinVar as [Benign]. Clinvar id is 1255317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.1796+76A>G		intron_variant	Intron 15 of 22	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.1751+76A>G		intron_variant	Intron 14 of 21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.1796+76A>G		intron_variant	Intron 15 of 22	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*1081+76A>G		intron_variant	Intron 15 of 22	1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.1796+76A>G		intron_variant	Intron 15 of 22			ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66641 AN: 151864 Hom.: 15179 Cov.: 32

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.450

GnomAD4 exome AF: 0.414 AC: 564070 AN: 1363810 Hom.: 118309 Cov.: 21 AF XY: 0.414 AC XY: 282596 AN XY: 682758

African (AFR) AF: 0.565 AC: 17709 AN: 31356

American (AMR) AF: 0.312 AC: 13502 AN: 43332

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 12738 AN: 25400

East Asian (EAS) AF: 0.305 AC: 11925 AN: 39080

South Asian (SAS) AF: 0.419 AC: 35162 AN: 83852

European-Finnish (FIN) AF: 0.388 AC: 20134 AN: 51952

Middle Eastern (MID) AF: 0.453 AC: 2536 AN: 5602

European-Non Finnish (NFE) AF: 0.415 AC: 425923 AN: 1026190

Other (OTH) AF: 0.428 AC: 24441 AN: 57046

GnomAD4 genome AF: 0.439 AC: 66731 AN: 151982 Hom.: 15213 Cov.: 32 AF XY: 0.433 AC XY: 32198 AN XY: 74284

African (AFR) AF: 0.561 AC: 23236 AN: 41436

American (AMR) AF: 0.338 AC: 5167 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1779 AN: 3470

East Asian (EAS) AF: 0.269 AC: 1389 AN: 5154

South Asian (SAS) AF: 0.409 AC: 1971 AN: 4822

European-Finnish (FIN) AF: 0.372 AC: 3929 AN: 10554

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27992 AN: 67966

Other (OTH) AF: 0.446 AC: 939 AN: 2104

Alfa AF: 0.433 Hom.: 2942

Bravo AF: 0.441

Asia WGS AF: 0.353 AC: 1233 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.2
DANN	Benign	0.67
PhyloP100		-0.086
Mutation Taster		=100/0	polymorphism (auto)

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: rs940864; hg19: chr7-143039311; COSMIC: COSV58369501;