chr17-39462763-C-A

Position:

• chr17-39462763-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016507.4(CDK12):​c.692C>A​(p.Ser231Tyr) 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. 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: 2.23

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18340504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK12	NM_016507.4	c.692C>A	p.Ser231Tyr	missense_variant	1/14	ENST00000447079.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK12	ENST00000447079.6	c.692C>A	p.Ser231Tyr	missense_variant	1/14	1	NM_016507.4	P4
CDK12	ENST00000430627.6	c.692C>A	p.Ser231Tyr	missense_variant	1/14	1		A1
CDK12	ENST00000584632.5	c.692C>A	p.Ser231Tyr	missense_variant	1/13	5
CDK12	ENST00000559663.2	c.692C>A	p.Ser231Tyr	missense_variant, NMD_transcript_variant	1/21	5

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 17, 2022

The c.692C>A (p.S231Y) alteration is located in exon 1 (coding exon 1) of the CDK12 gene. This alteration results from a C to A substitution at nucleotide position 692, causing the serine (S) at amino acid position 231 to be replaced by a tyrosine (Y). 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	0.20
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0049	T;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.69	.;N;N
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.10	.;N;N
REVEL	Benign	0.091
Sift	Benign	0.031	.;D;D
Sift4G	Uncertain	0.041	D;D;D
Polyphen		1.0, 0.99	.;D;D
Vest4		0.11, 0.17
MutPred		0.18		Gain of ubiquitination at K226 (P = 0.0563);Gain of ubiquitination at K226 (P = 0.0563);Gain of ubiquitination at K226 (P = 0.0563);
MVP		0.33
MPC		0.43
ClinPred		0.79	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.044

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: chr17-37619016; COSMIC: COSV71000381;