chr17-39462930-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016507.4(CDK12):ā€‹c.859T>Cā€‹(p.Ser287Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

CDK12
NM_016507.4 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.70
Variant links:
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]

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ACMG classification

Classification made for transcript

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=0.20509657).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CDK12NM_016507.4 linkuse as main transcriptc.859T>C p.Ser287Pro missense_variant 1/14 ENST00000447079.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDK12ENST00000447079.6 linkuse as main transcriptc.859T>C p.Ser287Pro missense_variant 1/141 NM_016507.4 P4Q9NYV4-1
CDK12ENST00000430627.6 linkuse as main transcriptc.859T>C p.Ser287Pro missense_variant 1/141 A1Q9NYV4-2
CDK12ENST00000584632.5 linkuse as main transcriptc.859T>C p.Ser287Pro missense_variant 1/135
CDK12ENST00000559663.2 linkuse as main transcriptc.859T>C p.Ser287Pro missense_variant, NMD_transcript_variant 1/215

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251412
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 22, 2023The c.859T>C (p.S287P) alteration is located in exon 1 (coding exon 1) of the CDK12 gene. This alteration results from a T to C substitution at nucleotide position 859, causing the serine (S) at amino acid position 287 to be replaced by a proline (P). 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
Benign
0.087
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.015
T;.;T
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.61
T;T;T
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
1.9
.;L;L
MutationTaster
Benign
0.98
D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.58
.;N;N
REVEL
Benign
0.12
Sift
Uncertain
0.0020
.;D;D
Sift4G
Uncertain
0.057
T;D;D
Polyphen
1.0, 0.99
.;D;D
Vest4
0.16, 0.24
MutPred
0.19
Loss of phosphorylation at S287 (P = 0.0013);Loss of phosphorylation at S287 (P = 0.0013);Loss of phosphorylation at S287 (P = 0.0013);
MVP
0.38
MPC
0.42
ClinPred
0.47
T
GERP RS
5.3
Varity_R
0.26
gMVP
0.36

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs762770417; hg19: chr17-37619183; API