Genetic Variant CLTCL1:p.Arg1620His (chr22-19180775-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_007098.4(CLTCL1):c.4859G>A(p.Arg1620His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00929 in 1,613,786 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0072 ( 17 hom., cov: 34)

Exomes 𝑓: 0.0095 ( 175 hom. )

Consequence

CLTCL1
NM_007098.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.293

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017917454).

BP6

Variant 22-19180775-C-T is Benign according to our data. Variant chr22-19180775-C-T is described in ClinVar as [Benign]. Clinvar id is 2652855.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00722 (1099/152316) while in subpopulation SAS AF= 0.0495 (239/4826). AF 95% confidence interval is 0.0444. There are 17 homozygotes in gnomad4. There are 573 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLTCL1	NM_007098.4 link	c.4859G>A	p.Arg1620His	missense_variant	Exon 31 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.4859G>A	p.Arg1620His	missense_variant	Exon 31 of 33	1	NM_007098.4	ENSP00000441158.1		P53675-1

Frequencies

GnomAD3 genomes

AF:

0.00725

AC:

1103

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00739

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.0106

Gnomad SAS

AF:

0.0501

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00742

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.0119

AC:

2961

AN:

249178

Hom.:

AF XY:

0.0140

AC XY:

1893

AN XY:

135204

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.00574

Gnomad ASJ exome

AF:

0.0207

Gnomad EAS exome

AF:

0.0103

Gnomad SAS exome

AF:

0.0472

Gnomad FIN exome

AF:

0.000836

Gnomad NFE exome

AF:

0.00712

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.00950

AC:

13886

AN:

1461470

Hom.:

175

Cov.:

AF XY:

0.0107

AC XY:

7747

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.00635

Gnomad4 ASJ exome

AF:

0.0203

Gnomad4 EAS exome

AF:

0.00668

Gnomad4 SAS exome

AF:

0.0458

Gnomad4 FIN exome

AF:

0.000826

Gnomad4 NFE exome

AF:

0.00717

Gnomad4 OTH exome

AF:

0.0106

GnomAD4 genome

AF:

0.00722

AC:

1099

AN:

152316

Hom.:

Cov.:

AF XY:

0.00769

AC XY:

573

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00738

Gnomad4 ASJ

AF:

0.0187

Gnomad4 EAS

AF:

0.0106

Gnomad4 SAS

AF:

0.0495

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00742

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.00813

Hom.:

Bravo

AF:

0.00652

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.000703

AC:

ESP6500EA

AF:

0.00787

AC:

ExAC

AF:

0.0120

AC:

1453

Asia WGS

AF:

0.0310

AC:

106

AN:

3478

EpiCase

AF:

0.00878

EpiControl

AF:

0.00883

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CLTCL1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.22

DANN

Benign

0.90

DEOGEN2

Benign

0.21

.;T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.86

D;D;D;D

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

.;L;.;.

PrimateAI

Benign

0.18

PROVEAN

Benign

-2.0

.;N;.;.

REVEL

Benign

0.16

Sift

Benign

0.054

.;T;.;.

Sift4G

Uncertain

0.056

T;T;T;T

Polyphen

0.016

B;B;.;.

Vest4

0.099

ClinPred

0.014

GERP RS

-5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.028

gMVP

0.47

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