chr17-59620165-C-T

Variant names:

• chr17-59620165-C-T
• rs2031319375
• NM_004859.4:c.34C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 56

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000273702 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20898023).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004859.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLTC	NM_004859.4	MANE Select	c.34C>T	p.His12Tyr	missense	Exon 1 of 32	NP_004850.1	Q00610-1
	CLTC	NM_001288653.2		c.34C>T	p.His12Tyr	missense	Exon 1 of 32	NP_001275582.1	A0A087WVQ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLTC	ENST00000269122.8	TSL:1 MANE Select	c.34C>T	p.His12Tyr	missense	Exon 1 of 32	ENSP00000269122.3	Q00610-1
	CLTC	ENST00000393043.5	TSL:1	c.34C>T	p.His12Tyr	missense	Exon 1 of 31	ENSP00000376763.1	Q00610-2
	CLTC	ENST00000700714.2		c.34C>T	p.His12Tyr	missense	Exon 1 of 34	ENSP00000515154.2	A0A8V8TQ18

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.071
Eigen_PC	Benign	0.071
FATHMM_MKL	Benign	0.39	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.19
Sift	Benign	0.77	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.49
MutPred		0.26		Loss of sheet (P = 0.1907)
MVP		0.55
MPC		1.5
ClinPred		0.91	D
GERP RS		4.7
PromoterAI		0.098	Neutral
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

Other links and lift over

dbSNP: rs2031319375; hg19: chr17-57697526;