chr17-59620135-G-C

Position:

• chr17-59620135-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_004859.4(CLTC):​c.4G>C​(p.Ala2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CLTC NM_004859.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.54

Genes affected

CLTC (HGNC:2092): (clathrin heavy chain) Clathrin is a major protein component of the cytoplasmic face of intracellular organelles, called coated vesicles and coated pits. These specialized organelles are involved in the intracellular trafficking of receptors and endocytosis of a variety of macromolecules. The basic subunit of the clathrin coat is composed of three heavy chains and three light chains. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity CLH1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CLTC. . Gene score misZ 7.7637 (greater than the threshold 3.09). Trascript score misZ 10.215 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant non-syndromic intellectual disability, undetermined early-onset epileptic encephalopathy, intellectual disability, autosomal dominant 56.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLTC	NM_004859.4	c.4G>C	p.Ala2Pro	missense_variant	1/32	ENST00000269122.8	NP_004850.1
CLTC	NM_001288653.2	c.4G>C	p.Ala2Pro	missense_variant	1/32		NP_001275582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLTC	ENST00000269122.8	c.4G>C	p.Ala2Pro	missense_variant	1/32	1	NM_004859.4	ENSP00000269122	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 24, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with CLTC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2 of the CLTC protein (p.Ala2Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T;.;D;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;M;M;.;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.6	.;D;D;.;.
REVEL	Benign	0.21
Sift	Uncertain	0.0080	.;D;D;.;.
Sift4G	Uncertain	0.0090	D;D;D;D;T
Polyphen		0.020, 0.99	.;B;D;.;.
Vest4		0.44
MutPred		0.48		Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);
MVP		0.66
MPC		2.6
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.54

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: rs1209338205; hg19: chr17-57697496;