rs1633399

Variant names:

• chr22-19196276-A-G
• rs1633399
• NM_007098.4:c.4181T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.059 (330 hom., cov: 33)
  • Exomes 𝑓: 0.066 (3364 hom.)
• Consequence: CLTCL1 NM_007098.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.61
• Publications: 30 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

ENSG00000286367 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 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 no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
CLTCL1	NM_007098.4	c.4181T>C	p.Ile1394Thr	missense_variant	Exon 26 of 33	ENST00000427926.6	NP_009029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLTCL1	ENST00000427926.6	c.4181T>C	p.Ile1394Thr	missense_variant	Exon 26 of 33	1	NM_007098.4	ENSP00000441158.1

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

GnomAD2 exomes AF: 0.0654 AC: 16226 AN: 248290 AF XY: 0.0635

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 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

African (AFR) AF: 0.0428 AC: 1434 AN: 33478

American (AMR) AF: 0.0960 AC: 4288 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0636 AC: 1661 AN: 26132

East Asian (EAS) AF: 0.0614 AC: 2437 AN: 39700

South Asian (SAS) AF: 0.0434 AC: 3743 AN: 86250

European-Finnish (FIN) AF: 0.0471 AC: 2487 AN: 52780

Middle Eastern (MID) AF: 0.105 AC: 604 AN: 5766

European-Non Finnish (NFE) AF: 0.0686 AC: 76296 AN: 1111726

Other (OTH) AF: 0.0626 AC: 3778 AN: 60356

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

African (AFR) AF: 0.0396 AC: 1644 AN: 41526

American (AMR) AF: 0.0830 AC: 1269 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 225 AN: 3470

East Asian (EAS) AF: 0.0492 AC: 254 AN: 5166

South Asian (SAS) AF: 0.0419 AC: 202 AN: 4826

European-Finnish (FIN) AF: 0.0452 AC: 480 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0688 AC: 4680 AN: 67996

Other (OTH) AF: 0.0744 AC: 157 AN: 2110

Alfa AF: 0.0679 Hom.: 1669

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: no assertion criteria provided

Submissions by phenotype

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	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.87
DEOGEN2	Benign	0.14	.;T;T;.
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;.;.
PhyloP100		4.6
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.2	.;D;.;.
REVEL	Benign	0.079
Sift	Benign	0.13	.;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
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: rs1633399; hg19: chr22-19183787; COSMIC: COSV54241792; COSMIC: COSV54241792;