rs61741615

Variant names:

• chr17-39526140-C-T
• rs61741615
• NM_016507.4:c.3584C>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1195T) has been classified 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:4 O:1
• Conservation: PhyloP100: 0.790
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016507.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK12	NM_016507.4	MANE Select	c.3584C>T	p.Thr1195Met	missense	Exon 13 of 14	NP_057591.2
	CDK12	NM_015083.4		c.3584C>T	p.Thr1195Met	missense	Exon 13 of 14	NP_055898.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK12	ENST00000447079.6	TSL:1 MANE Select	c.3584C>T	p.Thr1195Met	missense	Exon 13 of 14	ENSP00000398880.4
	CDK12	ENST00000430627.6	TSL:1	c.3584C>T	p.Thr1195Met	missense	Exon 13 of 14	ENSP00000407720.2
	CDK12	ENST00000922307.1		c.3506C>T	p.Thr1169Met	missense	Exon 12 of 13	ENSP00000592366.1

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

GnomAD2 exomes AF: 0.00230 AC: 578 AN: 251316 AF XY: 0.00169

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 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

African (AFR) AF: 0.0321 AC: 1075 AN: 33480

American (AMR) AF: 0.00172 AC: 77 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112012

Other (OTH) AF: 0.00210 AC: 127 AN: 60396

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

African (AFR) AF: 0.0321 AC: 1332 AN: 41552

American (AMR) AF: 0.00340 AC: 52 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00356 Hom.: 19

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CDK12-related disorder (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.79
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.080
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.039	D
Polyphen		0.0040	B
Vest4		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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

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