chr17-59620165-C-T

Position:

• chr17-59620165-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004859.4(CLTC):​c.34C>T​(p.His12Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: 2.59

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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20898023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLTC	NM_004859.4	c.34C>T	p.His12Tyr	missense_variant	1/32	ENST00000269122.8	NP_004850.1
CLTC	NM_001288653.2	c.34C>T	p.His12Tyr	missense_variant	1/32		NP_001275582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLTC	ENST00000269122.8	c.34C>T	p.His12Tyr	missense_variant	1/32	1	NM_004859.4	ENSP00000269122	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

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

GeneDx

May 10, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.0026	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.098	T;.;T;T;.
Eigen	Benign	-0.071
Eigen_PC	Benign	0.071
FATHMM_MKL	Benign	0.39	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	.;M;M;.;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	.;N;N;.;.
REVEL	Benign	0.19
Sift	Benign	0.77	.;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	.;B;B;.;.
Vest4		0.49
MutPred		0.26		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);
MVP		0.55
MPC		1.5
ClinPred		0.91	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.78

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: rs2031319375; hg19: chr17-57697526;