dbSNP rs121912799: CLCN1:p.Phe413Tyr (chr7-143332490-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000083.3(CLCN1):c.1238T>A(p.Phe413Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F413C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.80

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a helix (size 2) in uniprot entity CLCN1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000083.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-143332490-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3 link	c.1238T>A	p.Phe413Tyr	missense_variant	Exon 11 of 23	ENST00000343257.7	NP_000074.3	P35523
CLCN1	NR_046453.2 link	n.1343T>A		non_coding_transcript_exon_variant	Exon 11 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLCN1	ENST00000343257.7 link	c.1238T>A	p.Phe413Tyr	missense_variant	Exon 11 of 23	1	NM_000083.3	ENSP00000339867.2	P35523
CLCN1	ENST00000432192.6 link	n.*523T>A		non_coding_transcript_exon_variant	Exon 11 of 23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000432192.6 link	n.*523T>A		3_prime_UTR_variant	Exon 11 of 23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000650516.2 link	c.1238T>A	p.Phe413Tyr	missense_variant	Exon 11 of 23			ENSP00000498052.2	A0A3B3IU72

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461572

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.097

MetaRNN

Uncertain

0.58

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.63

Sift

Benign

0.13

Sift4G

Benign

0.20

Polyphen

0.97

Vest4

0.54

MutPred

0.56

Gain of catalytic residue at M414 (P = 0.032);

MVP

0.93

MPC

0.62

ClinPred

0.96

GERP RS

5.3

Varity_R

0.29

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over