rs61747413

Variant names:

• chr17-39519956-C-T
• rs61747413
• NM_016507.4:c.2964C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_016507.4(CDK12):​c.2964C>T​(p.Phe988Phe) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000443 in 1,613,708 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: CDK12 NM_016507.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.002238
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 1.92
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 17-39519956-C-T is Benign according to our data. Variant chr17-39519956-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 133856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.92 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK12	NM_016507.4	MANE Select	c.2964C>T	p.Phe988Phe	splice_region synonymous	Exon 11 of 14	NP_057591.2
	CDK12	NM_015083.4		c.2964C>T	p.Phe988Phe	splice_region synonymous	Exon 11 of 14	NP_055898.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK12	ENST00000447079.6	TSL:1 MANE Select	c.2964C>T	p.Phe988Phe	splice_region synonymous	Exon 11 of 14	ENSP00000398880.4
	CDK12	ENST00000430627.6	TSL:1	c.2964C>T	p.Phe988Phe	splice_region synonymous	Exon 11 of 14	ENSP00000407720.2
	CDK12	ENST00000584632.5	TSL:5	c.2961C>T	p.Phe987Phe	splice_region synonymous	Exon 11 of 13	ENSP00000464641.1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152058 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00882

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000625 AC: 157 AN: 251276 AF XY: 0.000449

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000225 AC: 329 AN: 1461532 Hom.: 1 Cov.: 31 AF XY: 0.000190 AC XY: 138 AN XY: 727076

African (AFR) AF: 0.00777 AC: 260 AN: 33474

American (AMR) AF: 0.000492 AC: 22 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111816

Other (OTH) AF: 0.000663 AC: 40 AN: 60374

GnomAD4 genome AF: 0.00254 AC: 386 AN: 152176 Hom.: 3 Cov.: 31 AF XY: 0.00257 AC XY: 191 AN XY: 74408

African (AFR) AF: 0.00882 AC: 366 AN: 41508

American (AMR) AF: 0.000982 AC: 15 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000616 Hom.: 2

Bravo AF: 0.00283

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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 specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		1.9
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.020		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: rs61747413; hg19: chr17-37676209;