rs190351859

chr22-19208261-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007098.4(CLTCL1):c.3493C>T(p.Arg1165Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,613,704 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1165H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (64 hom.)
• Consequence: CLTCL1 NM_007098.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.731

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=0.0048317313).
• BP6: Variant 22-19208261-G-A is Benign according to our data. Variant chr22-19208261-G-A is described in ClinVar as [Benign]. Clinvar id is 445797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00466 (709/152234) while in subpopulation AMR AF= 0.0383 (585/15288). AF 95% confidence interval is 0.0357. There are 19 homozygotes in gnomad4. There are 416 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLTCL1	NM_007098.4	c.3493C>T	p.Arg1165Cys	missense_variant	22/33	ENST00000427926.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLTCL1	ENST00000427926.6	c.3493C>T	p.Arg1165Cys	missense_variant	22/33	1	NM_007098.4	P1

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 709 AN: 152116 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0383

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00741 AC: 1847 AN: 249136 Hom.: 39 AF XY: 0.00575 AC XY: 777 AN XY: 135210

Gnomad AFR exome AF: 0.000969

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00345

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000328

Gnomad OTH exome AF: 0.00578

GnomAD4 exome AF: 0.00191 AC: 2790 AN: 1461470 Hom.: 64 Cov.: 32 AF XY: 0.00171 AC XY: 1242 AN XY: 726996

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.0483

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00610

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000193

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00466 AC: 709 AN: 152234 Hom.: 19 Cov.: 32 AF XY: 0.00559 AC XY: 416 AN XY: 74428

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.0383

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00308

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.000767 Hom.: 3

Bravo AF: 0.00672

ESP6500AA AF: 0.00272 AC: 10

ESP6500EA AF: 0.000489 AC: 4

ExAC AF: 0.00546 AC: 660

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Autism Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The homozygous p.Arg1165Cys variant, sometimes called p.Arg125Cys due to a difference in cDNA numbering, in CLTCL1 has been identified in 2 siblings from 1 family with autism (PMID: 22511880), and has been identified in >4% of Latino chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autism. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.070
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.23	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.30
MVP		0.47
ClinPred		0.10	T
GERP RS		3.2
Varity_R		0.39
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs190351859; hg19: chr22-19195771;