rs199652160

Positions:

chr22-19234688-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id 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/exons	MANE	UniProt
CLTCL1	NM_007098.4 linkuse as main transcript	c.988G>A	p.Glu330Lys	missense_variant	7/33	ENST00000427926.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLTCL1	ENST00000427926.6 linkuse as main transcript	c.988G>A	p.Glu330Lys	missense_variant	7/33	1	NM_007098.4	P1	P53675-1
CLTCL1	ENST00000621271.4 linkuse as main transcript	c.988G>A	p.Glu330Lys	missense_variant	7/32	1			P53675-2
CLTCL1	ENST00000615606.4 linkuse as main transcript	n.1008G>A		non_coding_transcript_exon_variant	7/30	1
CLTCL1	ENST00000617103.4 linkuse as main transcript	c.988G>A	p.Glu330Lys	missense_variant, NMD_transcript_variant	7/31	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

GnomAD3 exomes

AF:

0.000490

AC:

122

AN:

249198

Hom.:

AF XY:

0.000414

AC XY:

AN XY:

135192

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 SAS exome

AF:

0.0000654

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

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000961

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000765

Gnomad4 OTH exome

AF:

0.000663

GnomAD4 genome

AF:

0.000505

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000656

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

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	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. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Oct 29, 2015	- -

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

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

MutationTaster

Benign

1.0

D;D;D

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

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

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