15-44490988-C-G

Position:

• chr15-44490988-C-G

Variant summary

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

The NM_016396.3(CTDSPL2):​c.680C>G​(p.Pro227Arg) 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: CTDSPL2 NM_016396.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23

Genes affected

CTDSPL2 (HGNC:26936): (CTD small phosphatase like 2) Enables RNA polymerase II CTD heptapeptide repeat phosphatase activity. Predicted to act upstream of or within negative regulation of BMP signaling pathway; positive regulation of protein export from nucleus; and protein dephosphorylation. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CTDSPL2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTDSPL2	NM_016396.3	c.680C>G	p.Pro227Arg	missense_variant	5/13	ENST00000260327.9	NP_057480.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTDSPL2	ENST00000260327.9	c.680C>G	p.Pro227Arg	missense_variant	5/13	1	NM_016396.3	ENSP00000260327.4
CTDSPL2	ENST00000558966.5	c.680C>G	p.Pro227Arg	missense_variant	5/13	1		ENSP00000452837.1
CTDSPL2	ENST00000558373.5	c.475+4288C>G		intron_variant		1		ENSP00000453051.1
CTDSPL2	ENST00000561189.1	n.-4C>G		upstream_gene_variant		5

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The c.680C>G (p.P227R) alteration is located in exon 5 (coding exon 4) of the CTDSPL2 gene. This alteration results from a C to G substitution at nucleotide position 680, causing the proline (P) at amino acid position 227 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.073	T;T
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.31		Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);
MVP		0.24
MPC		0.52
ClinPred		0.95	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.38
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-44783186;