Genetic Variant CLHC1:p.Arg382Gln (chr2-55181606-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_152385.4(CLHC1):c.1145G>A(p.Arg382Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,612,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R382W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CLHC1
NM_152385.4 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.28

Publications

3 publications found

Variant links:

Genes affected

CLHC1 (HGNC:26453): (clathrin heavy chain linker domain containing 1)

CLHC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 2-55181606-C-T is Pathogenic according to our data. Variant chr2-55181606-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 183280.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.021851927). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLHC1	NM_152385.4 link	c.1145G>A	p.Arg382Gln	missense_variant	Exon 10 of 13	ENST00000401408.6	NP_689598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLHC1	ENST00000401408.6 link	c.1145G>A	p.Arg382Gln	missense_variant	Exon 10 of 13	1	NM_152385.4	ENSP00000384869.1

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00481

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000268

AC:

AN:

249746

AF XY:

0.000163

show subpopulations

Gnomad AFR exome

AF:

0.00407

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000175

AC:

255

AN:

1460018

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

726230

show subpopulations

African (AFR)

AF:

0.00444

AC:

148

AN:

33364

American (AMR)

AF:

0.0000678

AC:

AN:

44228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00169

AC:

AN:

39632

South Asian (SAS)

AF:

0.00

AC:

AN:

85748

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111494

Other (OTH)

AF:

0.000199

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00133

AC:

202

AN:

152218

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00477

AC:

198

AN:

41524

American (AMR)

AF:

0.000196

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000389

Hom.:

Bravo

AF:

0.00141

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000445

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Waddling gait;CN228301:Marked Hypotonia

Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.053

T;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.70

LIST_S2

Benign

0.0

.;T;D

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Pathogenic

3.5

M;M;.

PhyloP100

2.3

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.3

D;D;D

Sift

Uncertain

0.011

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.74

ClinPred

0.26

GERP RS

5.8

Varity_R

0.36

gMVP

0.46

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over