chr7-143316255-T-A

Variant names:

• chr7-143316255-T-A
• rs1194717455
• NM_000083.3:c.43T>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000083.3(CLCN1):​c.43T>A​(p.Trp15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3527437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.43T>A	p.Trp15Arg	missense_variant	Exon 1 of 23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.145T>A		non_coding_transcript_exon_variant	Exon 1 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.43T>A	p.Trp15Arg	missense_variant	Exon 1 of 23	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000650516.2	c.43T>A	p.Trp15Arg	missense_variant	Exon 1 of 23			ENSP00000498052.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.62	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.90	.;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	.;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.032	.;D
Polyphen		0.84	.;P
Vest4		0.62
MutPred		0.29		Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);
MVP		0.96
MPC		1.0
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.43
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1194717455; hg19: chr7-143013348;