7-143320714-G-T

Variant names:

• chr7-143320714-G-T
• rs10282312
• NM_000083.3:c.352G>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000083.3(CLCN1):​c.352G>T​(p.Gly118Trp) variant causes a missense change. The variant allele was found at a frequency of 0.977 in 1,613,664 control chromosomes in the GnomAD database, including 769,979 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G118G) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.98 (73648 hom., cov: 29)
  • Exomes 𝑓: 0.98 (696331 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 6.18
• Publications: 36 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 -17 ACMG points.

• PM1: In a helix (size 36) in uniprot entity CLCN1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000083.3
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=5.607244E-7).
• BP6: Variant 7-143320714-G-T is Benign according to our data. Variant chr7-143320714-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 802378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

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.352G>T	p.Gly118Trp	missense	Exon 3 of 23	NP_000074.3
	CLCN1	NR_046453.2		n.454G>T		non_coding_transcript_exon	Exon 3 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.352G>T	p.Gly118Trp	missense	Exon 3 of 23	ENSP00000339867.2
	CLCN1	ENST00000432192.6	TSL:1	n.118G>T		non_coding_transcript_exon	Exon 2 of 23	ENSP00000395949.2
	CLCN1	ENST00000650516.2		c.352G>T	p.Gly118Trp	missense	Exon 3 of 23	ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.984 AC: 149559 AN: 152008 Hom.: 73590 Cov.: 29

Gnomad AFR AF: 0.996

Gnomad AMI AF: 0.897

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 0.983

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 0.985

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.974

Gnomad OTH AF: 0.990

GnomAD2 exomes AF: 0.985 AC: 247777 AN: 251494 AF XY: 0.985

Gnomad AFR exome AF: 0.996

Gnomad AMR exome AF: 0.995

Gnomad ASJ exome AF: 0.979

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.980

Gnomad NFE exome AF: 0.976

Gnomad OTH exome AF: 0.985

GnomAD4 exome AF: 0.976 AC: 1426547 AN: 1461538 Hom.: 696331 Cov.: 39 AF XY: 0.977 AC XY: 710223 AN XY: 727110

African (AFR) AF: 0.997 AC: 33366 AN: 33474

American (AMR) AF: 0.994 AC: 44474 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.980 AC: 25613 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39696 AN: 39698

South Asian (SAS) AF: 0.998 AC: 86075 AN: 86252

European-Finnish (FIN) AF: 0.979 AC: 52324 AN: 53420

Middle Eastern (MID) AF: 0.997 AC: 5749 AN: 5768

European-Non Finnish (NFE) AF: 0.972 AC: 1080179 AN: 1111686

Other (OTH) AF: 0.978 AC: 59071 AN: 60382

GnomAD4 genome AF: 0.984 AC: 149676 AN: 152126 Hom.: 73648 Cov.: 29 AF XY: 0.985 AC XY: 73258 AN XY: 74354

African (AFR) AF: 0.996 AC: 41295 AN: 41480

American (AMR) AF: 0.991 AC: 15152 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.983 AC: 3411 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5164 AN: 5164

South Asian (SAS) AF: 0.998 AC: 4812 AN: 4820

European-Finnish (FIN) AF: 0.985 AC: 10420 AN: 10580

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.974 AC: 66222 AN: 68016

Other (OTH) AF: 0.991 AC: 2090 AN: 2110

Alfa AF: 0.979 Hom.: 103813

Bravo AF: 0.985

TwinsUK AF: 0.974 AC: 3613

ALSPAC AF: 0.972 AC: 3748

ESP6500AA AF: 0.995 AC: 4385

ESP6500EA AF: 0.975 AC: 8385

ExAC AF: 0.986 AC: 119721

Asia WGS AF: 0.999 AC: 3474 AN: 3478

EpiCase AF: 0.977

EpiControl AF: 0.981

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Congenital myotonia, autosomal recessive form (2)
-	-	2	Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (2)
-	-	1	Congenital myotonia, autosomal dominant form (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-3.1	N
PhyloP100		6.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	12	N
REVEL	Uncertain	0.29
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.091
MPC		0.22
ClinPred		0.022	T
GERP RS		5.0
Varity_R		0.32
gMVP		0.78
Mutation Taster		=93/7	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: rs10282312; hg19: chr7-143017807; COSMIC: COSV107447151; COSMIC: COSV107447151;