17-39531224-G-T

Variant names:

• chr17-39531224-G-T
• rs186043011
• NM_016507.4:c.4381G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016507.4(CDK12):​c.4381G>T​(p.Gly1461Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000851 in 1,516,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1461R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.384
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024345458).

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.4381G>T	p.Gly1461Cys	missense	Exon 14 of 14	NP_057591.2	Q9NYV4-1
	CDK12	NM_015083.4		c.4354G>T	p.Gly1452Cys	missense	Exon 14 of 14	NP_055898.1	Q9NYV4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK12	ENST00000447079.6	TSL:1 MANE Select	c.4381G>T	p.Gly1461Cys	missense	Exon 14 of 14	ENSP00000398880.4	Q9NYV4-1
	CDK12	ENST00000430627.6	TSL:1	c.4354G>T	p.Gly1452Cys	missense	Exon 14 of 14	ENSP00000407720.2	Q9NYV4-2
	CDK12	ENST00000922307.1		c.4303G>T	p.Gly1435Cys	missense	Exon 13 of 13	ENSP00000592366.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000748 AC: 13 AN: 173822 AF XY: 0.0000651

Gnomad AFR exome AF: 0.0000691

Gnomad AMR exome AF: 0.000497

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000235

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000836 AC: 114 AN: 1364112 Hom.: 0 Cov.: 33 AF XY: 0.0000853 AC XY: 57 AN XY: 668332

African (AFR) AF: 0.000232 AC: 7 AN: 30178

American (AMR) AF: 0.000672 AC: 19 AN: 28264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19844

East Asian (EAS) AF: 0.00 AC: 0 AN: 38732

South Asian (SAS) AF: 0.0000144 AC: 1 AN: 69386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49764

Middle Eastern (MID) AF: 0.000189 AC: 1 AN: 5290

European-Non Finnish (NFE) AF: 0.0000741 AC: 79 AN: 1066550

Other (OTH) AF: 0.000125 AC: 7 AN: 56104

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74442

African (AFR) AF: 0.0000722 AC: 3 AN: 41536

American (AMR) AF: 0.000262 AC: 4 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000733 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000758 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.83	T
PhyloP100		0.38
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.062
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.013	D
Polyphen		0.12	B
Vest4		0.17
MVP		0.57
MPC		0.64
ClinPred		0.068	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.22
Mutation Taster		=91/9	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: rs186043011; hg19: chr17-37687477;