18-79679953-G-T

Position:

• chr18-79679953-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004715.5(CTDP1):​c.6G>T​(p.Glu2Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000162 in 1,230,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: CTDP1 NM_004715.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

Genes affected

CTDP1 (HGNC:2498): (CTD phosphatase subunit 1) This gene encodes a protein which interacts with the carboxy-terminus of the RAP74 subunit of transcription initiation factor TFIIF, and functions as a phosphatase that processively dephosphorylates the C-terminus of POLR2A (a subunit of RNA polymerase II), making it available for initiation of gene expression. Mutations in this gene are associated with congenital cataracts, facial dysmorphism and neuropathy syndrome (CCFDN). Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.190337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTDP1	NM_004715.5	c.6G>T	p.Glu2Asp	missense_variant	1/13	ENST00000613122.5	NP_004706.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTDP1	ENST00000613122.5	c.6G>T	p.Glu2Asp	missense_variant	1/13	1	NM_004715.5	ENSP00000484525.2
CTDP1	ENST00000075430.11	c.6G>T	p.Glu2Asp	missense_variant	1/12	1		ENSP00000075430.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000162 AC: 2 AN: 1230946 Hom.: 0 Cov.: 29 AF XY: 0.00000165 AC XY: 1 AN XY: 605622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000485

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Mar 18, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with CTDP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 2 of the CTDP1 protein (p.Glu2Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.40	T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.96	.;N
REVEL	Benign	0.036
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.11	T;T
Polyphen		0.99	D;B
Vest4		0.089
MutPred		0.18		Loss of catalytic residue at E2 (P = 0.2948);Loss of catalytic residue at E2 (P = 0.2948);
MVP		0.30
ClinPred		0.55	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.25
gMVP		0.51

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: rs1468065862; hg19: chr18-77439953;