rs1633399

chr22-19196276-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_007098.4(CLTCL1):c.4181T>C(p.Ile1394Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0655 in 1,613,068 control chromosomes in the GnomAD database, including 3,694 homozygotes. In-silico tool predicts 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 0.059 (330 hom., cov: 33)
  • Exomes 𝑓: 0.066 (3364 hom.)
• Consequence: CLTCL1 NM_007098.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.61

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=0.0033106506).
• BP6: Variant 22-19196276-A-G is Benign according to our data. Variant chr22-19196276-A-G is described in ClinVar as [Benign]. Clinvar id is 3059365.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLTCL1	NM_007098.4	c.4181T>C	p.Ile1394Thr	missense_variant	26/33	ENST00000427926.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLTCL1	ENST00000427926.6	c.4181T>C	p.Ile1394Thr	missense_variant	26/33	1	NM_007098.4	P1

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8957 AN: 152088 Hom.: 330 Cov.: 33

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0827

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.0491

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0747

GnomAD3 exomes AF: 0.0654 AC: 16226 AN: 248290 Hom.: 559 AF XY: 0.0635 AC XY: 8558 AN XY: 134758

Gnomad AFR exome AF: 0.0412

Gnomad AMR exome AF: 0.0994

Gnomad ASJ exome AF: 0.0628

Gnomad EAS exome AF: 0.0493

Gnomad SAS exome AF: 0.0434

Gnomad FIN exome AF: 0.0469

Gnomad NFE exome AF: 0.0700

Gnomad OTH exome AF: 0.0745

GnomAD4 exome AF: 0.0662 AC: 96728 AN: 1460862 Hom.: 3364 Cov.: 31 AF XY: 0.0655 AC XY: 47586 AN XY: 726748

Gnomad4 AFR exome AF: 0.0428

Gnomad4 AMR exome AF: 0.0960

Gnomad4 ASJ exome AF: 0.0636

Gnomad4 EAS exome AF: 0.0614

Gnomad4 SAS exome AF: 0.0434

Gnomad4 FIN exome AF: 0.0471

Gnomad4 NFE exome AF: 0.0686

Gnomad4 OTH exome AF: 0.0626

GnomAD4 genome AF: 0.0589 AC: 8967 AN: 152206 Hom.: 330 Cov.: 33 AF XY: 0.0584 AC XY: 4346 AN XY: 74428

Gnomad4 AFR AF: 0.0396

Gnomad4 AMR AF: 0.0830

Gnomad4 ASJ AF: 0.0648

Gnomad4 EAS AF: 0.0492

Gnomad4 SAS AF: 0.0419

Gnomad4 FIN AF: 0.0452

Gnomad4 NFE AF: 0.0688

Gnomad4 OTH AF: 0.0744

Alfa AF: 0.0697 Hom.: 867

Bravo AF: 0.0624

TwinsUK AF: 0.0696 AC: 258

ALSPAC AF: 0.0719 AC: 277

ESP6500AA AF: 0.0388 AC: 157

ESP6500EA AF: 0.0647 AC: 544

ExAC AF: 0.0645 AC: 7807

Asia WGS AF: 0.0530 AC: 186 AN: 3478

EpiCase AF: 0.0797

EpiControl AF: 0.0761

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CLTCL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Benign	0.87
Eigen	Benign	-0.041
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D;D;D;D
MetaRNN	Benign	0.0033	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.;.
MutationTaster	Benign	0.000018	P;P;P
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.21	T;T;D;T
Polyphen		0.0030	B;B;.;.
Vest4		0.29
ClinPred		0.025	T
GERP RS		3.6
Varity_R		0.091
gMVP		0.46

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: rs1633399; hg19: chr22-19183787; COSMIC: COSV54241792; COSMIC: COSV54241792;