NM_018249.6:c.1712T>C

Variant names:

• chr9-120477365-A-G
• rs41296081
• NM_018249.6:c.1712T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018249.6(CDK5RAP2):​c.1712T>C​(p.Leu571Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00792 in 1,610,960 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L571L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (71 hom.)
• Consequence: CDK5RAP2 NM_018249.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 5.14
• Publications: 11 publications found

Genes affected

CDK5RAP2 (HGNC:18672): (CDK5 regulatory subunit associated protein 2) This gene encodes a regulator of CDK5 (cyclin-dependent kinase 5) activity. The protein encoded by this gene is localized to the centrosome and Golgi complex, interacts with CDK5R1 and pericentrin (PCNT), plays a role in centriole engagement and microtubule nucleation, and has been linked to primary microcephaly and Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

CDK5RAP2 Gene-Disease associations (from GenCC):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• microcephaly 3, primary, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• corpus callosum, agenesis of

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072303414).
• BP6: Variant 9-120477365-A-G is Benign according to our data. Variant chr9-120477365-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00758 (1155/152356) while in subpopulation NFE AF = 0.0116 (789/68026). AF 95% confidence interval is 0.0109. There are 7 homozygotes in GnomAd4. There are 593 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018249.6. 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
	CDK5RAP2	NM_018249.6	MANE Select	c.1712T>C	p.Leu571Pro	missense	Exon 15 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.1712T>C	p.Leu571Pro	missense	Exon 15 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.1712T>C	p.Leu571Pro	missense	Exon 15 of 37	NP_001397922.1	Q96SN8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.1712T>C	p.Leu571Pro	missense	Exon 15 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.1712T>C	p.Leu571Pro	missense	Exon 15 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.*456T>C		non_coding_transcript_exon	Exon 16 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.00759 AC: 1155 AN: 152238 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0201

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00844 AC: 2120 AN: 251252 AF XY: 0.00876

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00796 AC: 11610 AN: 1458604 Hom.: 71 Cov.: 30 AF XY: 0.00811 AC XY: 5883 AN XY: 725838

African (AFR) AF: 0.00102 AC: 34 AN: 33440

American (AMR) AF: 0.00288 AC: 129 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00540 AC: 141 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86190

European-Finnish (FIN) AF: 0.0220 AC: 1169 AN: 53160

Middle Eastern (MID) AF: 0.00781 AC: 45 AN: 5764

European-Non Finnish (NFE) AF: 0.00867 AC: 9617 AN: 1109262

Other (OTH) AF: 0.00758 AC: 457 AN: 60272

GnomAD4 genome AF: 0.00758 AC: 1155 AN: 152356 Hom.: 7 Cov.: 32 AF XY: 0.00796 AC XY: 593 AN XY: 74512

African (AFR) AF: 0.00118 AC: 49 AN: 41590

American (AMR) AF: 0.00418 AC: 64 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 22 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

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

European-Finnish (FIN) AF: 0.0201 AC: 214 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 789 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.0108 Hom.: 54

Bravo AF: 0.00620

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00868 AC: 1054

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0114

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Microcephaly 3, primary, autosomal recessive (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.070	T
Polyphen		1.0	D
Vest4		0.39
MVP		0.67
MPC		0.54
ClinPred		0.019	T
GERP RS		5.7
Varity_R		0.80
gMVP		0.63
Mutation Taster		=98/2	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: rs41296081; hg19: chr9-123239643;