rs712952

Positions:

• chr22-19210439-G-A
• chr22-19210439-G-C
• chr22-19210439-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000427926.6(CLTCL1):​c.3136C>T​(p.Arg1046Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0655 in 1,613,798 control chromosomes in the GnomAD database, including 3,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1046P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.059 (328 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3368 hom.)
• Consequence: CLTCL1 ENST00000427926.6 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.59

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042405725).
• BP6: Variant 22-19210439-G-A is Benign according to our data. Variant chr22-19210439-G-A is described in ClinVar as [Benign]. Clinvar id is 3060068.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLTCL1	NM_007098.4	c.3136C>T	p.Arg1046Cys	missense_variant	20/33	ENST00000427926.6	NP_009029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLTCL1	ENST00000427926.6	c.3136C>T	p.Arg1046Cys	missense_variant	20/33	1	NM_007098.4	ENSP00000441158	P1
CLTCL1	ENST00000621271.4	c.3136C>T	p.Arg1046Cys	missense_variant	20/32	1		ENSP00000485020
CLTCL1	ENST00000615606.4	n.3156C>T		non_coding_transcript_exon_variant	20/30	1
CLTCL1	ENST00000617103.4	c.3136C>T	p.Arg1046Cys	missense_variant, NMD_transcript_variant	20/31	1		ENSP00000480709

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8951 AN: 152066 Hom.: 328 Cov.: 32

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0829

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.0493

Gnomad SAS AF: 0.0415

Gnomad FIN AF: 0.0451

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0746

GnomAD3 exomes AF: 0.0653 AC: 16275 AN: 249214 Hom.: 573 AF XY: 0.0635 AC XY: 8580 AN XY: 135196

Gnomad AFR exome AF: 0.0412

Gnomad AMR exome AF: 0.0994

Gnomad ASJ exome AF: 0.0629

Gnomad EAS exome AF: 0.0495

Gnomad SAS exome AF: 0.0435

Gnomad FIN exome AF: 0.0467

Gnomad NFE exome AF: 0.0699

Gnomad OTH exome AF: 0.0740

GnomAD4 exome AF: 0.0662 AC: 96688 AN: 1461614 Hom.: 3368 Cov.: 34 AF XY: 0.0654 AC XY: 47557 AN XY: 727096

Gnomad4 AFR exome AF: 0.0428

Gnomad4 AMR exome AF: 0.0961

Gnomad4 ASJ exome AF: 0.0635

Gnomad4 EAS exome AF: 0.0615

Gnomad4 SAS exome AF: 0.0435

Gnomad4 FIN exome AF: 0.0471

Gnomad4 NFE exome AF: 0.0685

Gnomad4 OTH exome AF: 0.0625

GnomAD4 genome AF: 0.0589 AC: 8961 AN: 152184 Hom.: 328 Cov.: 32 AF XY: 0.0585 AC XY: 4351 AN XY: 74404

Gnomad4 AFR AF: 0.0395

Gnomad4 AMR AF: 0.0831

Gnomad4 ASJ AF: 0.0648

Gnomad4 EAS AF: 0.0495

Gnomad4 SAS AF: 0.0421

Gnomad4 FIN AF: 0.0451

Gnomad4 NFE AF: 0.0688

Gnomad4 OTH AF: 0.0743

Alfa AF: 0.0692 Hom.: 784

Bravo AF: 0.0624

TwinsUK AF: 0.0696 AC: 258

ALSPAC AF: 0.0719 AC: 277

ESP6500AA AF: 0.0389 AC: 164

ESP6500EA AF: 0.0646 AC: 547

ExAC AF: 0.0645 AC: 7807

Asia WGS AF: 0.0530 AC: 186 AN: 3478

EpiCase AF: 0.0797

EpiControl AF: 0.0759

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CLTCL1-related disorder Benign:1

Benign, no assertion criteria provided

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	0.082
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.6	H;H
MutationTaster	Benign	3.6e-7	P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.6	.;D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.41
ClinPred		0.081	T
GERP RS		2.8
Varity_R		0.70
gMVP		0.60

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: rs712952; hg19: chr22-19197949; COSMIC: COSV54232190; COSMIC: COSV54232190;