rs190351859

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007098.4(CLTCL1):c.3493C>T(p.Arg1165Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,613,704 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1165H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0047 ( 19 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 64 hom. )

Consequence

CLTCL1
NM_007098.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.731

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048317313).

BP6

Variant 22-19208261-G-A is Benign according to our data. Variant chr22-19208261-G-A is described in ClinVar as Benign. ClinVar VariationId is 445797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00466 (709/152234) while in subpopulation AMR AF = 0.0383 (585/15288). AF 95% confidence interval is 0.0357. There are 19 homozygotes in GnomAd4. There are 416 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLTCL1	NM_007098.4 link	c.3493C>T	p.Arg1165Cys	missense_variant	Exon 22 of 33	ENST00000427926.6	NP_009029.3	P53675-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLTCL1	ENST00000427926.6 link	c.3493C>T	p.Arg1165Cys	missense_variant	Exon 22 of 33	1	NM_007098.4	ENSP00000441158.1		P53675-1

Frequencies

GnomAD3 genomes

AF:

0.00466

AC:

709

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0383

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00741

AC:

1847

AN:

249136

AF XY:

0.00575

show subpopulations

Gnomad AFR exome

AF:

0.000969

Gnomad AMR exome

AF:

0.0487

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00345

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000328

Gnomad OTH exome

AF:

0.00578

GnomAD4 exome

AF:

0.00191

AC:

2790

AN:

1461470

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1242

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33478

American (AMR)

AF:

0.0483

AC:

2159

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00610

AC:

242

AN:

39700

South Asian (SAS)

AF:

0.000452

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53212

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000193

AC:

215

AN:

1111846

Other (OTH)

AF:

0.00179

AC:

108

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

155

310

465

620

775

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00466

AC:

709

AN:

152234

Hom.:

Cov.:

AF XY:

0.00559

AC XY:

416

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41536

American (AMR)

AF:

0.0383

AC:

585

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00308

AC:

AN:

5188

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000324

AC:

AN:

68004

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00119

Hom.:

Bravo

AF:

0.00672

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.000489

AC:

ExAC

AF:

0.00546

AC:

660

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 20, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autism

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Arg1165Cys variant, sometimes called p.Arg125Cys due to a difference in cDNA numbering, in CLTCL1 has been identified in 2 siblings from 1 family with autism (PMID: 22511880), and has been identified in >4% of Latino chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autism. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.070

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Pathogenic

3.7

H;H

PhyloP100

0.73

PrimateAI

Benign

0.23

PROVEAN

Pathogenic

-6.0

.;D

REVEL

Benign

0.23

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

D;D

Vest4

0.30

MVP

0.47

ClinPred

0.10

GERP RS

3.2

Varity_R

0.39

gMVP

0.52

Mutation Taster

=99/1

polymorphism

(source)

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

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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