NM_016507.4:c.1913G>C

Variant names:

• chr17-39471745-G-C
• rs587778183
• NM_016507.4:c.1913G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016507.4(CDK12):​c.1913G>C​(p.Gly638Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,612,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 4.50
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19254044).

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.1913G>C	p.Gly638Ala	missense	Exon 2 of 14	NP_057591.2	Q9NYV4-1
	CDK12	NM_015083.4		c.1913G>C	p.Gly638Ala	missense	Exon 2 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.1913G>C	p.Gly638Ala	missense	Exon 2 of 14	ENSP00000398880.4	Q9NYV4-1
	CDK12	ENST00000430627.6	TSL:1	c.1913G>C	p.Gly638Ala	missense	Exon 2 of 14	ENSP00000407720.2	Q9NYV4-2
	CDK12	ENST00000922307.1		c.1913G>C	p.Gly638Ala	missense	Exon 2 of 13	ENSP00000592366.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152090 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249538 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

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: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460054 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726212

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.0000898 AC: 4 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111032

Other (OTH) AF: 0.0000166 AC: 1 AN: 60302

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152090 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.000131 AC: 2 AN: 15256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

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	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0085	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.082
Sift	Benign	0.032	D
Sift4G	Benign	0.26	T
Polyphen		0.72	P
Vest4		0.36
MutPred		0.21		Loss of stability (P = 0.1353)
MVP		0.56
MPC		1.1
ClinPred		0.31	T
GERP RS		4.7
PromoterAI		-0.0089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs587778183; hg19: chr17-37627998;