rs807459

Variant names:

• chr22-19235829-T-C
• rs807459
• NM_007098.4:c.836A>G

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: 2.85
• Publications: 27 publications found

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]

CLTCL1 Gene-Disease associations (from GenCC):

• congenital insensitivity to pain with severe intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CLTCL1	NM_007098.4	c.836A>G	p.Tyr279Cys	missense_variant	Exon 6 of 33	ENST00000427926.6	NP_009029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLTCL1	ENST00000427926.6	c.836A>G	p.Tyr279Cys	missense_variant	Exon 6 of 33	1	NM_007098.4	ENSP00000441158.1
CLTCL1	ENST00000621271.4	c.836A>G	p.Tyr279Cys	missense_variant	Exon 6 of 32	1		ENSP00000485020.1
CLTCL1	ENST00000615606.4	n.856A>G		non_coding_transcript_exon_variant	Exon 6 of 30	1
CLTCL1	ENST00000617103.4	n.836A>G		non_coding_transcript_exon_variant	Exon 6 of 31	1		ENSP00000480709.1

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

GnomAD2 exomes AF: 0.0663 AC: 16508 AN: 249136 AF XY: 0.0644

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 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

African (AFR) AF: 0.0527 AC: 1765 AN: 33478

American (AMR) AF: 0.0969 AC: 4335 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0635 AC: 1660 AN: 26134

East Asian (EAS) AF: 0.0613 AC: 2434 AN: 39698

South Asian (SAS) AF: 0.0449 AC: 3870 AN: 86252

European-Finnish (FIN) AF: 0.0471 AC: 2517 AN: 53402

Middle Eastern (MID) AF: 0.106 AC: 611 AN: 5768

European-Non Finnish (NFE) AF: 0.0685 AC: 76158 AN: 1111624

Other (OTH) AF: 0.0639 AC: 3858 AN: 60360

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

African (AFR) AF: 0.0490 AC: 2037 AN: 41542

American (AMR) AF: 0.0850 AC: 1300 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 225 AN: 3472

East Asian (EAS) AF: 0.0499 AC: 259 AN: 5186

South Asian (SAS) AF: 0.0439 AC: 212 AN: 4826

European-Finnish (FIN) AF: 0.0449 AC: 476 AN: 10610

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.0688 AC: 4680 AN: 68026

Other (OTH) AF: 0.0766 AC: 162 AN: 2114

Alfa AF: 0.0687 Hom.: 1213

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CLTCL1-related disorder Benign:1

Mar 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		2.9
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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