22-19210439-G-T

Position:

• chr22-19210439-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000427926.6(CLTCL1):​c.3136C>A​(p.Arg1046Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1046C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLTCL1 ENST00000427926.6 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLTCL1	NM_007098.4	c.3136C>A	p.Arg1046Ser	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>A	p.Arg1046Ser	missense_variant	20/33	1	NM_007098.4	ENSP00000441158	P1
CLTCL1	ENST00000621271.4	c.3136C>A	p.Arg1046Ser	missense_variant	20/32	1		ENSP00000485020
CLTCL1	ENST00000615606.4	n.3156C>A		non_coding_transcript_exon_variant	20/30	1
CLTCL1	ENST00000617103.4	c.3136C>A	p.Arg1046Ser	missense_variant, NMD_transcript_variant	20/31	1		ENSP00000480709

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.0071	T
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	0.00011	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-4.4	.;D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.84	P;P
Vest4		0.73
MutPred		0.53		Loss of catalytic residue at R1046 (P = 0.1203);Loss of catalytic residue at R1046 (P = 0.1203);
MVP		0.43
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.75
gMVP		0.64

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;