dbSNP rs712952: CLTCL1:p.Arg1046Cys (chr22-19210439-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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

GnomAD3 exomes

AF:

0.0653

AC:

16275

AN:

249214

Hom.:

573

AF XY:

0.0635

AC XY:

8580

AN XY:

135196

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 SAS exome

AF:

0.0435

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

Gnomad4 AFR exome

AF:

0.0428

Gnomad4 AMR exome

AF:

0.0961

Gnomad4 ASJ exome

AF:

0.0635

Gnomad4 EAS exome

AF:

0.0615

Gnomad4 SAS exome

AF:

0.0435

Gnomad4 FIN exome

AF:

0.0471

Gnomad4 NFE exome

AF:

0.0685

Gnomad4 OTH exome

AF:

0.0625

GnomAD4 genome

AF:

0.0589

AC:

8961

AN:

152184

Hom.:

328

Cov.:

AF XY:

0.0585

AC XY:

4351

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0395

Gnomad4 AMR

AF:

0.0831

Gnomad4 ASJ

AF:

0.0648

Gnomad4 EAS

AF:

0.0495

Gnomad4 SAS

AF:

0.0421

Gnomad4 FIN

AF:

0.0451

Gnomad4 NFE

AF:

0.0688

Gnomad4 OTH

AF:

0.0743

Alfa

AF:

0.0692

Hom.:

784

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over