22-19191342-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007098.4(CLTCL1):c.4285C>T(p.Arg1429Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: CLTCL1 NM_007098.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0409953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLTCL1	NM_007098.4	c.4285C>T	p.Arg1429Trp	missense_variant	27/33	ENST00000427926.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLTCL1	ENST00000427926.6	c.4285C>T	p.Arg1429Trp	missense_variant	27/33	1	NM_007098.4	P1

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000185 AC: 46 AN: 249278 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135244

Gnomad AFR exome AF: 0.00220

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000746 AC: 109 AN: 1461692 Hom.: 0 Cov.: 30 AF XY: 0.0000880 AC XY: 64 AN XY: 727126

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74440

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.000774

ESP6500AA AF: 0.00128 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000190 AC: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 29, 2016

The R1429W variant in the CLTCL1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1429W variant was not observed with any significant frequency in approximately 6100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1429W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution is located in a region involved in binding clathrin light chains and occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on this information, we interpret R1429W as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.041	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.5	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.40	B;B;.;.
Vest4		0.93
MVP		0.55
ClinPred		0.16	T
GERP RS		3.6
Varity_R		0.38
gMVP		0.72

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

Other links and lift over

dbSNP: rs190366603; hg19: chr22-19178854; COSMIC: COSV54232397; COSMIC: COSV54232397;