rs61741615

chr17-39526140-C-T

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.3584C>T(p.Thr1195Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,614,192 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (22 hom.)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.790

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=0.002410978).
• BP6: Variant 17-39526140-C-T is Benign according to our data. Variant chr17-39526140-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 133859.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 = 0.00928 (1413/152302) while in subpopulation AFR AF= 0.0321 (1332/41552). AF 95% confidence interval is 0.0306. There are 19 homozygotes in gnomad4. There are 697 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1388 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK12	NM_016507.4	c.3584C>T	p.Thr1195Met	missense_variant	13/14	ENST00000447079.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK12	ENST00000447079.6	c.3584C>T	p.Thr1195Met	missense_variant	13/14	1	NM_016507.4	P4
CDK12	ENST00000430627.6	c.3584C>T	p.Thr1195Met	missense_variant	13/14	1		A1
CDK12	ENST00000584632.5	c.3581C>T	p.Thr1194Met	missense_variant	13/13	5
CDK12	ENST00000559663.2	c.3584C>T	p.Thr1195Met	missense_variant, NMD_transcript_variant	13/21	5

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1388 AN: 152184 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00230 AC: 578 AN: 251316 Hom.: 8 AF XY: 0.00169 AC XY: 229 AN XY: 135822

Gnomad AFR exome AF: 0.0322

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000910 AC: 1330 AN: 1461890 Hom.: 22 Cov.: 32 AF XY: 0.000789 AC XY: 574 AN XY: 727248

Gnomad4 AFR exome AF: 0.0321

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00928 AC: 1413 AN: 152302 Hom.: 19 Cov.: 32 AF XY: 0.00936 AC XY: 697 AN XY: 74484

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00171 Hom.: 5

Bravo AF: 0.0108

ESP6500AA AF: 0.0329 AC: 145

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00273 AC: 332

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

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

Apr 04, 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	0.081
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.022	T;.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.40	T
Sift4G	Uncertain	0.039	D;T;T
Polyphen		0.0040, 0.0020	.;B;B
Vest4		0.14, 0.14
MVP		0.41
MPC		0.51
ClinPred		0.017	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.24

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: rs61741615; hg19: chr17-37682393; COSMIC: COSV70999311; COSMIC: COSV70999311;