rs712952

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_007098.4(CLTCL1):c.3136C>T(p.Arg1046Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0655 in 1,613,798 control chromosomes in the GnomAD database, including 3,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1046P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.059 ( 328 hom., cov: 32)

Exomes 𝑓: 0.066 ( 3368 hom. )

Consequence

CLTCL1
NM_007098.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 5.59

Publications

30 publications found

Variant links:

Genes affected

CLTCL1 (HGNC:2093): (clathrin heavy chain like 1) This gene is a member of the clathrin heavy chain family and encodes a major protein of the polyhedral coat of coated pits and vesicles. Chromosomal aberrations involving this gene are associated with meningioma, DiGeorge syndrome, and velo-cardio-facial syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

CLTCL1 Gene-Disease associations (from GenCC):

congenital insensitivity to pain with severe intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
multiple congenital anomalies/dysmorphic syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CLTCL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042405725).

BP6

Variant 22-19210439-G-A is Benign according to our data. Variant chr22-19210439-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060068.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLTCL1	NM_007098.4 link	c.3136C>T	p.Arg1046Cys	missense_variant	Exon 20 of 33	ENST00000427926.6	NP_009029.3	P53675-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLTCL1	ENST00000427926.6 link	c.3136C>T	p.Arg1046Cys	missense_variant	Exon 20 of 33	1	NM_007098.4	ENSP00000441158.1	P53675-1
CLTCL1	ENST00000621271.4 link	c.3136C>T	p.Arg1046Cys	missense_variant	Exon 20 of 32	1		ENSP00000485020.1	P53675-2
CLTCL1	ENST00000615606.4 link	n.3156C>T		non_coding_transcript_exon_variant	Exon 20 of 30	1
CLTCL1	ENST00000617103.4 link	n.3136C>T		non_coding_transcript_exon_variant	Exon 20 of 31	1		ENSP00000480709.1	A0A087WX41

Frequencies

GnomAD3 genomes

AF:

0.0589

AC:

8951

AN:

152066

Hom.:

328

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0395

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0829

Gnomad ASJ

AF:

0.0648

Gnomad EAS

AF:

0.0493

Gnomad SAS

AF:

0.0415

Gnomad FIN

AF:

0.0451

Gnomad MID

AF:

0.150

Gnomad NFE

AF:

0.0688

Gnomad OTH

AF:

0.0746

GnomAD2 exomes

AF:

0.0653

AC:

16275

AN:

249214

AF XY:

0.0635

show subpopulations

Gnomad AFR exome

AF:

0.0412

Gnomad AMR exome

AF:

0.0994

Gnomad ASJ exome

AF:

0.0629

Gnomad EAS exome

AF:

0.0495

Gnomad FIN exome

AF:

0.0467

Gnomad NFE exome

AF:

0.0699

Gnomad OTH exome

AF:

0.0740

GnomAD4 exome

AF:

0.0662

AC:

96688

AN:

1461614

Hom.:

3368

Cov.:

AF XY:

0.0654

AC XY:

47557

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.0428

AC:

1434

AN:

33480

American (AMR)

AF:

0.0961

AC:

4296

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0635

AC:

1660

AN:

26134

East Asian (EAS)

AF:

0.0615

AC:

2441

AN:

39700

South Asian (SAS)

AF:

0.0435

AC:

3748

AN:

86254

European-Finnish (FIN)

AF:

0.0471

AC:

2516

AN:

53396

Middle Eastern (MID)

AF:

0.105

AC:

607

AN:

5766

European-Non Finnish (NFE)

AF:

0.0685

AC:

76213

AN:

1111796

Other (OTH)

AF:

0.0625

AC:

3773

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

4775

9550

14326

19101

23876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2824

5648

8472

11296

14120

<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:

0.0589

AC:

8961

AN:

152184

Hom.:

328

Cov.:

AF XY:

0.0585

AC XY:

4351

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0395

AC:

1640

AN:

41532

American (AMR)

AF:

0.0831

AC:

1271

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0648

AC:

225

AN:

3472

East Asian (EAS)

AF:

0.0495

AC:

256

AN:

5176

South Asian (SAS)

AF:

0.0421

AC:

203

AN:

4818

European-Finnish (FIN)

AF:

0.0451

AC:

478

AN:

10588

Middle Eastern (MID)

AF:

0.154

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0688

AC:

4676

AN:

67996

Other (OTH)

AF:

0.0743

AC:

157

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

432

864

1297

1729

2161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.0676

Hom.:

1462

Bravo

AF:

0.0624

TwinsUK

AF:

0.0696

AC:

258

ALSPAC

AF:

0.0719

AC:

277

ESP6500AA

AF:

0.0389

AC:

164

ESP6500EA

AF:

0.0646

AC:

547

ExAC

AF:

0.0645

AC:

7807

Asia WGS

AF:

0.0530

AC:

186

AN:

3478

EpiCase

AF:

0.0797

EpiControl

AF:

0.0759

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CLTCL1-related disorder

Benign:1

Mar 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Pathogenic

3.6

H;H

PhyloP100

5.6

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-6.6

.;D

REVEL

Benign

0.17

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.41

ClinPred

0.081

GERP RS

2.8

Varity_R

0.70

gMVP

0.60

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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