22-19180775-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0072 (17 hom., cov: 34)
  • Exomes 𝑓: 0.0095 (175 hom.)
• Consequence: CLTCL1 NM_007098.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.293

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 Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLTCL1	NM_007098.4	c.4859G>A	p.Arg1620His	missense_variant	31/33	ENST00000427926.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLTCL1	ENST00000427926.6	c.4859G>A	p.Arg1620His	missense_variant	31/33	1	NM_007098.4	P1

Frequencies

GnomAD3 genomes AF: 0.00725 AC: 1103 AN: 152198 Hom.: 17 Cov.: 34

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

GnomAD3 exomes AF: 0.0119 AC: 2961 AN: 249178 Hom.: 59 AF XY: 0.0140 AC XY: 1893 AN XY: 135204

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 SAS exome AF: 0.0472

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.: 31 AF XY: 0.0107 AC XY: 7747 AN XY: 727030

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00635

Gnomad4 ASJ exome AF: 0.0203

Gnomad4 EAS exome AF: 0.00668

Gnomad4 SAS exome AF: 0.0458

Gnomad4 FIN exome AF: 0.000826

Gnomad4 NFE exome AF: 0.00717

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.00722 AC: 1099 AN: 152316 Hom.: 17 Cov.: 34 AF XY: 0.00769 AC XY: 573 AN XY: 74494

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.0495

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00742

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00813 Hom.: 7

Bravo AF: 0.00652

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.000703 AC: 3

ESP6500EA AF: 0.00787 AC: 67

ExAC AF: 0.0120 AC: 1453

Asia WGS AF: 0.0310 AC: 106 AN: 3478

EpiCase AF: 0.00878

EpiControl AF: 0.00883

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

CLTCL1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.22
Dann	Benign	0.90
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.86	D;D;D;D
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.18	T
Sift4G	Uncertain	0.056	T;T;T;T
Polyphen		0.016	B;B;.;.
Vest4		0.099
ClinPred		0.014	T
GERP RS		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.028
gMVP		0.47

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: rs5748024; hg19: chr22-19168288; COSMIC: COSV53206853; COSMIC: COSV53206853;