17-59674813-A-G

Position:

• chr17-59674813-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004859.4(CLTC):​c.2531A>G​(p.Glu844Gly) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: CLTC NM_004859.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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]

CLTC (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• 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.2531A>G	p.Glu844Gly	missense_variant	16/32	ENST00000269122.8	NP_004850.1
CLTC	NM_001288653.2	c.2543A>G	p.Glu848Gly	missense_variant	16/32		NP_001275582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLTC	ENST00000269122.8	c.2531A>G	p.Glu844Gly	missense_variant	16/32	1	NM_004859.4	ENSP00000269122.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

CLTC: PM2, PP2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.3	.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	.;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.026	.;D;D
Sift4G	Uncertain	0.036	D;D;D
Polyphen		0.0020, 0.36	.;B;B
Vest4		0.72
MutPred		0.60		.;Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.81
MPC		2.5
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.52
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-57752174;