chr17-39462148-G-A

Position:

• chr17-39462148-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016507.4(CDK12):​c.77G>A​(p.Gly26Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.70

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27409515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK12	NM_016507.4	c.77G>A	p.Gly26Glu	missense_variant	1/14	ENST00000447079.6	NP_057591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK12	ENST00000447079.6	c.77G>A	p.Gly26Glu	missense_variant	1/14	1	NM_016507.4	ENSP00000398880.4
CDK12	ENST00000430627.6	c.77G>A	p.Gly26Glu	missense_variant	1/14	1		ENSP00000407720.2
CDK12	ENST00000584632.5	c.77G>A	p.Gly26Glu	missense_variant	1/13	5		ENSP00000464641.1
CDK12	ENST00000559663.2	n.77G>A		non_coding_transcript_exon_variant	1/21	5		ENSP00000453329.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Nov 22, 2024

The p.G26E variant (also known as c.77G>A), located in coding exon 1 of the CDK12 gene, results from a G to A substitution at nucleotide position 77. The glycine at codon 26 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	0.0062	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0055	T;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.69	.;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.20	.;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0040	.;D;D
Sift4G	Benign	1.0	T;T;T
Polyphen		1.0, 1.0	.;D;D
Vest4		0.28, 0.35
MutPred		0.21		Gain of solvent accessibility (P = 0.024);Gain of solvent accessibility (P = 0.024);Gain of solvent accessibility (P = 0.024);
MVP		0.49
MPC		0.43
ClinPred		0.87	D
GERP RS		4.7
Varity_R		0.17
gMVP		0.047

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: chr17-37618401;