Genetic Variant CLTCL1:p.Val1592Met (chr22-19183443-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007098.4(CLTCL1):c.4774G>A(p.Val1592Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,613,660 control chromosomes in the GnomAD database, including 307 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. V1592L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0095 ( 34 hom., cov: 33)

Exomes 𝑓: 0.011 ( 273 hom. )

Consequence

CLTCL1
NM_007098.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.00200

Publications

14 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023112595).

BP6

Variant 22-19183443-C-T is Benign according to our data. Variant chr22-19183443-C-T is described in ClinVar as Benign. ClinVar VariationId is 1262625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.063 is higher than 0.05.

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.4774G>A	p.Val1592Met	missense	Exon 30 of 33	NP_009029.3	P53675-1
	CLTCL1	NM_001835.4		c.4603G>A	p.Val1535Met	missense	Exon 29 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.4774G>A	p.Val1592Met	missense	Exon 30 of 33	ENSP00000441158.1	P53675-1
CLTCL1	ENST00000621271.4	TSL:1	c.4603G>A	p.Val1535Met	missense	Exon 29 of 32	ENSP00000485020.1	P53675-2
CLTCL1	ENST00000615606.4	TSL:1	n.4867G>A		non_coding_transcript_exon	Exon 29 of 30

Frequencies

GnomAD3 genomes

AF:

0.00951

AC:

1447

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00792

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.0689

Gnomad SAS

AF:

0.0542

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00745

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0169

AC:

4207

AN:

248308

AF XY:

0.0185

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.00589

Gnomad ASJ exome

AF:

0.0219

Gnomad EAS exome

AF:

0.0763

Gnomad FIN exome

AF:

0.000835

Gnomad NFE exome

AF:

0.00708

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0114

AC:

16695

AN:

1461328

Hom.:

273

Cov.:

AF XY:

0.0125

AC XY:

9079

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33480

American (AMR)

AF:

0.00646

AC:

289

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0218

AC:

571

AN:

26136

East Asian (EAS)

AF:

0.0677

AC:

2689

AN:

39700

South Asian (SAS)

AF:

0.0472

AC:

4067

AN:

86252

European-Finnish (FIN)

AF:

0.000829

AC:

AN:

53048

Middle Eastern (MID)

AF:

0.0277

AC:

160

AN:

5768

European-Non Finnish (NFE)

AF:

0.00719

AC:

7990

AN:

1111860

Other (OTH)

AF:

0.0139

AC:

840

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1032

2064

3095

4127

5159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

380

760

1140

1520

1900

<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:

0.00947

AC:

1442

AN:

152332

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

774

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41564

American (AMR)

AF:

0.00791

AC:

121

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3472

East Asian (EAS)

AF:

0.0689

AC:

357

AN:

5184

South Asian (SAS)

AF:

0.0536

AC:

259

AN:

4828

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00745

AC:

507

AN:

68034

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

155

233

310

388

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:

0.00612

Hom.:

Bravo

AF:

0.00910

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.000930

AC:

ESP6500EA

AF:

0.00814

AC:

ExAC

AF:

0.0166

AC:

2013

EpiCase

AF:

0.00883

EpiControl

AF:

0.00883

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.011

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.051

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.6

PhyloP100

0.0020

PrimateAI

Benign

0.24

PROVEAN

Benign

1.2

REVEL

Benign

0.034

Sift

Benign

0.47

Sift4G

Benign

0.28

Polyphen

0.0020

Vest4

0.096

ClinPred

0.00044

GERP RS

-6.2

Varity_R

0.023

gMVP

0.28

Mutation Taster

=100/0

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