rs807459

Positions:

• chr22-19235829-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007098.4(CLTCL1):​c.836A>G​(p.Tyr279Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0661 in 1,613,704 control chromosomes in the GnomAD database, including 3,740 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 0.062 (352 hom., cov: 32)
  • Exomes 𝑓: 0.067 (3388 hom.)
• Consequence: CLTCL1 NM_007098.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.85

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009658188).
• BP6: Variant 22-19235829-T-C is Benign according to our data. Variant chr22-19235829-T-C is described in ClinVar as [Benign]. Clinvar id is 1230843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLTCL1	NM_007098.4	c.836A>G	p.Tyr279Cys	missense_variant	6/33	ENST00000427926.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLTCL1	ENST00000427926.6	c.836A>G	p.Tyr279Cys	missense_variant	6/33	1	NM_007098.4	P1
CLTCL1	ENST00000621271.4	c.836A>G	p.Tyr279Cys	missense_variant	6/32	1
CLTCL1	ENST00000615606.4	n.856A>G		non_coding_transcript_exon_variant	6/30	1
CLTCL1	ENST00000617103.4	c.836A>G	p.Tyr279Cys	missense_variant, NMD_transcript_variant	6/31	1

Frequencies

GnomAD3 genomes AF: 0.0617 AC: 9388 AN: 152156 Hom.: 351 Cov.: 32

Gnomad AFR AF: 0.0489

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0847

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.0498

Gnomad SAS AF: 0.0435

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0770

GnomAD3 exomes AF: 0.0663 AC: 16508 AN: 249136 Hom.: 578 AF XY: 0.0644 AC XY: 8703 AN XY: 135152

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.0627

Gnomad EAS exome AF: 0.0492

Gnomad SAS exome AF: 0.0455

Gnomad FIN exome AF: 0.0466

Gnomad NFE exome AF: 0.0699

Gnomad OTH exome AF: 0.0750

GnomAD4 exome AF: 0.0665 AC: 97208 AN: 1461430 Hom.: 3388 Cov.: 31 AF XY: 0.0658 AC XY: 47850 AN XY: 727014

Gnomad4 AFR exome AF: 0.0527

Gnomad4 AMR exome AF: 0.0969

Gnomad4 ASJ exome AF: 0.0635

Gnomad4 EAS exome AF: 0.0613

Gnomad4 SAS exome AF: 0.0449

Gnomad4 FIN exome AF: 0.0471

Gnomad4 NFE exome AF: 0.0685

Gnomad4 OTH exome AF: 0.0639

GnomAD4 genome AF: 0.0618 AC: 9407 AN: 152274 Hom.: 352 Cov.: 32 AF XY: 0.0611 AC XY: 4552 AN XY: 74448

Gnomad4 AFR AF: 0.0490

Gnomad4 AMR AF: 0.0850

Gnomad4 ASJ AF: 0.0648

Gnomad4 EAS AF: 0.0499

Gnomad4 SAS AF: 0.0439

Gnomad4 FIN AF: 0.0449

Gnomad4 NFE AF: 0.0688

Gnomad4 OTH AF: 0.0766

Alfa AF: 0.0705 Hom.: 591

Bravo AF: 0.0659

TwinsUK AF: 0.0696 AC: 258

ALSPAC AF: 0.0719 AC: 277

ESP6500AA AF: 0.0499 AC: 202

ESP6500EA AF: 0.0649 AC: 544

ExAC AF: 0.0657 AC: 7942

Asia WGS AF: 0.0570 AC: 199 AN: 3478

EpiCase AF: 0.0797

EpiControl AF: 0.0759

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 03, 2018

- -

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	0.099
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.64
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0097	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.0011	P;P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.8	.;D
REVEL	Benign	0.15
Sift	Benign	0.076	.;T
Sift4G	Uncertain	0.033	D;D
Polyphen		0.0010	B;P
Vest4		0.27
ClinPred		0.087	T
GERP RS		0.069
Varity_R		0.087
gMVP		0.55

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: rs807459; hg19: chr22-19223352; COSMIC: COSV54232219; COSMIC: COSV54232219;