rs199652160

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP5_ModerateBP4

The NM_007098.4(CLTCL1):c.988G>A(p.Glu330Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000633 in 1,613,948 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00065 ( 1 hom. )

Consequence

CLTCL1
NM_007098.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 4.32

Publications

11 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: Uncertain_significance. The variant received 1 ACMG points.

PP5

Variant 22-19234688-C-T is Pathogenic according to our data. Variant chr22-19234688-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 372327.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.2646821). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLTCL1	NM_007098.4 link	c.988G>A	p.Glu330Lys	missense_variant	Exon 7 of 33	ENST00000427926.6	NP_009029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CLTCL1	ENST00000427926.6 link	c.988G>A	p.Glu330Lys	missense_variant	Exon 7 of 33	1	NM_007098.4	ENSP00000441158.1
CLTCL1	ENST00000621271.4 link	c.988G>A	p.Glu330Lys	missense_variant	Exon 7 of 32	1		ENSP00000485020.1
CLTCL1	ENST00000615606.4 link	n.1008G>A		non_coding_transcript_exon_variant	Exon 7 of 30	1
CLTCL1	ENST00000617103.4 link	n.988G>A		non_coding_transcript_exon_variant	Exon 7 of 31	1		ENSP00000480709.1

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000490

AC:

122

AN:

249198

AF XY:

0.000414

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.000840

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000690

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000646

AC:

944

AN:

1461620

Hom.:

Cov.:

AF XY:

0.000648

AC XY:

471

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33478

American (AMR)

AF:

0.000961

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000765

AC:

851

AN:

1111816

Other (OTH)

AF:

0.000663

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.000505

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41568

American (AMR)

AF:

0.00222

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000689

Hom.:

Bravo

AF:

0.000990

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000744

AC:

ESP6500EA

AF:

0.000358

AC:

ExAC

AF:

0.000513

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Sep 29, 2016

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The E330K variant in the CLTCL1 gene has been reported previously, in the homozygous state, in three siblingswith significant intellectual disability, global developmental delay, absent pain sensation, self mutilating behavior,ophthalmological abnormalities, hypotonia, bone abnormalities, dysmorphic features, and brain abnormalities onMRI, with childhood death in two of the three siblings (Nahorski et al., 2015). The variant has also been reported inthe presence of another CLTCL1 variant in one individual with autism (Chahrour et al., 2012). The E330K variantwas not observed with any significant frequency in approximately 6200 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. The E330K variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition that is conserved across species and in silico analysis predicts this variant is probably damaging to theprotein structure/function. Therefore, we interpret E330K as a likely pathogenic variant, however, the possibility itmay be a rare benign variant cannot be excluded. -

Oct 29, 2015

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.0043

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

4.3

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.5

.;D

REVEL

Benign

0.21

Sift

Uncertain

0.0050

.;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.80

P;P

Vest4

0.80

MVP

0.40

ClinPred

0.13

GERP RS

3.3

Varity_R

0.35

gMVP

0.72

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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