rs61747430

Variant names:

• chr17-39525947-A-G
• rs61747430
• NM_016507.4:c.3391A>G
• CDK12 p.Ile1131Val

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.3391A>G​(p.Ile1131Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,614,184 control chromosomes in the GnomAD database, including 37 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1131N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0088 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (18 hom.)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 1.07
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022045374).
• BP6: Variant 17-39525947-A-G is Benign according to our data. Variant chr17-39525947-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133857.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 = 0.00882 (1344/152296) while in subpopulation AFR AF = 0.0306 (1273/41560). AF 95% confidence interval is 0.0292. There are 19 homozygotes in GnomAd4. There are 628 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.3391A>G	p.Ile1131Val	missense	Exon 13 of 14	NP_057591.2	Q9NYV4-1
	CDK12	NM_015083.4		c.3391A>G	p.Ile1131Val	missense	Exon 13 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.3391A>G	p.Ile1131Val	missense	Exon 13 of 14	ENSP00000398880.4	Q9NYV4-1
	CDK12	ENST00000430627.6	TSL:1	c.3391A>G	p.Ile1131Val	missense	Exon 13 of 14	ENSP00000407720.2	Q9NYV4-2
	CDK12	ENST00000922307.1		c.3313A>G	p.Ile1105Val	missense	Exon 12 of 13	ENSP00000592366.1

Frequencies

GnomAD3 genomes AF: 0.00883 AC: 1344 AN: 152178 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

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: 0.0000735

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00241 AC: 605 AN: 251406 AF XY: 0.00167

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000866 AC: 1266 AN: 1461888 Hom.: 18 Cov.: 32 AF XY: 0.000708 AC XY: 515 AN XY: 727244

African (AFR) AF: 0.0312 AC: 1043 AN: 33478

American (AMR) AF: 0.00179 AC: 80 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1112010

Other (OTH) AF: 0.00179 AC: 108 AN: 60396

GnomAD4 genome AF: 0.00882 AC: 1344 AN: 152296 Hom.: 19 Cov.: 32 AF XY: 0.00843 AC XY: 628 AN XY: 74472

African (AFR) AF: 0.0306 AC: 1273 AN: 41560

American (AMR) AF: 0.00373 AC: 57 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00655 Hom.: 7

Bravo AF: 0.0107

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.73
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.16	N
PhyloP100		1.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.13
Sift	Benign	0.21	T
Sift4G	Benign	1.0	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.015
gMVP		0.13
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61747430;

hg19: chr17-37682200;

COSMIC: COSV104713587;