22-19180775-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict 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. R1620C) has been classified as Uncertain significance.

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

Publications

16 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 links:

LINC01311 (HGNC:50503): (long intergenic non-protein coding RNA 1311)

LINC01311 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007098.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLTCL1	NM_007098.4	MANE Select	c.4859G>A	p.Arg1620His	missense	Exon 31 of 33	NP_009029.3	P53675-1
	CLTCL1	NM_001835.4		c.4688G>A	p.Arg1563His	missense	Exon 30 of 32	NP_001826.3	P53675-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLTCL1	ENST00000427926.6	TSL:1 MANE Select	c.4859G>A	p.Arg1620His	missense	Exon 31 of 33	ENSP00000441158.1	P53675-1
CLTCL1	ENST00000621271.4	TSL:1	c.4688G>A	p.Arg1563His	missense	Exon 30 of 32	ENSP00000485020.1	P53675-2
CLTCL1	ENST00000615606.4	TSL:1	n.4952G>A		non_coding_transcript_exon	Exon 30 of 30

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

GnomAD2 exomes

AF:

0.0119

AC:

2961

AN:

249178

AF XY:

0.0140

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 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

African (AFR)

AF:

0.00128

AC:

AN:

33480

American (AMR)

AF:

0.00635

AC:

284

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0203

AC:

531

AN:

26126

East Asian (EAS)

AF:

0.00668

AC:

265

AN:

39700

South Asian (SAS)

AF:

0.0458

AC:

3949

AN:

86252

European-Finnish (FIN)

AF:

0.000826

AC:

AN:

53278

Middle Eastern (MID)

AF:

0.0279

AC:

161

AN:

5766

European-Non Finnish (NFE)

AF:

0.00717

AC:

7969

AN:

1111794

Other (OTH)

AF:

0.0106

AC:

640

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

727

1453

2180

2906

3633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.00722

AC:

1099

AN:

152316

Hom.:

Cov.:

AF XY:

0.00769

AC XY:

573

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41580

American (AMR)

AF:

0.00738

AC:

113

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3472

East Asian (EAS)

AF:

0.0106

AC:

AN:

5188

South Asian (SAS)

AF:

0.0495

AC:

239

AN:

4826

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00742

AC:

505

AN:

68014

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00776

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.22

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.21

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

PhyloP100

0.29

PrimateAI

Benign

0.18

PROVEAN

Benign

-2.0

REVEL

Benign

0.16

Sift

Benign

0.054

Sift4G

Uncertain

0.056

Polyphen

0.016

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

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over