rs56362165

chr17-39526122-T-Achr17-39526122-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016507.4(CDK12):c.3566T>A(p.Leu1189Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,614,206 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1189R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0070 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (10 hom.)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.557

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021578074).
• BP6: Variant 17-39526122-T-A is Benign according to our data. Variant chr17-39526122-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 133860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00698 (1063/152312) while in subpopulation AFR AF= 0.0246 (1022/41562). AF 95% confidence interval is 0.0233. There are 14 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1061 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK12	NM_016507.4	c.3566T>A	p.Leu1189Gln	missense_variant	13/14	ENST00000447079.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK12	ENST00000447079.6	c.3566T>A	p.Leu1189Gln	missense_variant	13/14	1	NM_016507.4	P4
CDK12	ENST00000430627.6	c.3566T>A	p.Leu1189Gln	missense_variant	13/14	1		A1
CDK12	ENST00000584632.5	c.3563T>A	p.Leu1188Gln	missense_variant	13/13	5
CDK12	ENST00000559663.2	c.3566T>A	p.Leu1189Gln	missense_variant, NMD_transcript_variant	13/21	5

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 1061 AN: 152194 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00180 AC: 452 AN: 251326 Hom.: 3 AF XY: 0.00131 AC XY: 178 AN XY: 135820

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000809 AC: 1182 AN: 1461894 Hom.: 10 Cov.: 32 AF XY: 0.000682 AC XY: 496 AN XY: 727248

Gnomad4 AFR exome AF: 0.0281

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000746

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00698 AC: 1063 AN: 152312 Hom.: 14 Cov.: 32 AF XY: 0.00647 AC XY: 482 AN XY: 74494

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.00824

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00220 AC: 267

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CDK12-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	12
Dann	Benign	0.89
DEOGEN2	Benign	0.0052	T;.;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.65	T;T;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.93	N;N
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.67	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.18, 0.16
MVP		0.21
MPC		0.19
ClinPred		0.0084	T
GERP RS		-0.036
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.042
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

LitVar

Other links and lift over

dbSNP: rs56362165; hg19: chr17-37682375; COSMIC: COSV104713510; COSMIC: COSV104713510;