Genetic Variant NM_016507.4:c.1855A>T (chr17-39471687-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_016507.4(CDK12):c.1855A>T(p.Ile619Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDK12
NM_016507.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.83

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]

CDK12 links:

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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=0.20266694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK12	NM_016507.4 link	c.1855A>T	p.Ile619Phe	missense_variant	Exon 2 of 14	ENST00000447079.6	NP_057591.2	Q9NYV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK12	ENST00000447079.6 link	c.1855A>T	p.Ile619Phe	missense_variant	Exon 2 of 14	1	NM_016507.4	ENSP00000398880.4		Q9NYV4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727228

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.019

T;.;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.8

.;L;L

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.95

.;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0010

.;D;D

Sift4G

Benign

0.066

T;T;T

Polyphen

0.90, 0.84

.;P;P

Vest4

0.39, 0.40

MutPred

0.23

.;Loss of methylation at K623 (P = 0.0934);Loss of methylation at K623 (P = 0.0934);

MVP

0.58

MPC

0.92

ClinPred

0.72

GERP RS

5.8

Varity_R

0.21

gMVP

0.22

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over