17-39471411-C-A

Variant names:

• chr17-39471411-C-A
• rs587778182
• NM_016507.4:c.1579C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016507.4(CDK12):​c.1579C>A​(p.Pro527Thr) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P527S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.54
• Publications: 2 publications found

Genes affected

CDK12 (HGNC:24224): (cyclin dependent kinase 12) Enables RNA polymerase II CTD heptapeptide repeat kinase activity and cyclin binding activity. Involved in phosphorylation of RNA polymerase II C-terminal domain; protein autophosphorylation; and regulation of MAP kinase activity. Located in nuclear speck. Part of cyclin K-CDK12 complex. [provided by Alliance of Genome Resources, Apr 2022]

CDK12 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

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=0.23790777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK12	NM_016507.4	c.1579C>A	p.Pro527Thr	missense_variant	Exon 2 of 14	ENST00000447079.6	NP_057591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK12	ENST00000447079.6	c.1579C>A	p.Pro527Thr	missense_variant	Exon 2 of 14	1	NM_016507.4	ENSP00000398880.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.0070	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.080	T;.;T
Eigen	Benign	0.10
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.1	.;M;M
PhyloP100		2.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.3	.;N;D
REVEL	Benign	0.11
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.79, 0.68	.;P;P
Vest4		0.32, 0.35
MutPred		0.26		.;Gain of phosphorylation at P527 (P = 0.0039);Gain of phosphorylation at P527 (P = 0.0039);
MVP		0.45
MPC		1.1
ClinPred		0.84	D
GERP RS		5.0
PromoterAI		-0.0026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.036

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

Other links and lift over

dbSNP: rs587778182; hg19: chr17-37627664;