NM_018249.6:c.-19T>C

Variant names:

• chr9-120579997-A-G
• rs932974
• NM_018249.6:c.-19T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018249.6(CDK5RAP2):​c.-19T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,581,864 control chromosomes in the GnomAD database, including 779,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (71102 hom., cov: 36)
  • Exomes 𝑓: 1.0 (708453 hom.)
• Consequence: CDK5RAP2 NM_018249.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0760
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.98).
• BP6: Variant 9-120579997-A-G is Benign according to our data. Variant chr9-120579997-A-G is described in ClinVar as Benign. ClinVar VariationId is 95895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

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.-19T>C		5_prime_UTR	Exon 1 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.-19T>C		5_prime_UTR	Exon 1 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.-19T>C		5_prime_UTR	Exon 1 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.-19T>C		5_prime_UTR	Exon 1 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.-19T>C		5_prime_UTR	Exon 1 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.-19T>C		non_coding_transcript_exon	Exon 1 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.965 AC: 146884 AN: 152240 Hom.: 71060 Cov.: 36

Gnomad AFR AF: 0.881

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.974

GnomAD2 exomes AF: 0.989 AC: 241561 AN: 244164 AF XY: 0.992

Gnomad AFR exome AF: 0.873

Gnomad AMR exome AF: 0.989

Gnomad ASJ exome AF: 0.997

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.995 AC: 1422906 AN: 1429506 Hom.: 708453 Cov.: 24 AF XY: 0.996 AC XY: 710004 AN XY: 712974

African (AFR) AF: 0.876 AC: 28762 AN: 32840

American (AMR) AF: 0.989 AC: 43947 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 25832 AN: 25896

East Asian (EAS) AF: 1.00 AC: 39425 AN: 39428

South Asian (SAS) AF: 1.00 AC: 85290 AN: 85316

European-Finnish (FIN) AF: 1.00 AC: 53147 AN: 53148

Middle Eastern (MID) AF: 0.982 AC: 5598 AN: 5702

European-Non Finnish (NFE) AF: 0.999 AC: 1082310 AN: 1083576

Other (OTH) AF: 0.990 AC: 58595 AN: 59174

GnomAD4 genome AF: 0.965 AC: 146983 AN: 152358 Hom.: 71102 Cov.: 36 AF XY: 0.965 AC XY: 71919 AN XY: 74498

African (AFR) AF: 0.881 AC: 36613 AN: 41568

American (AMR) AF: 0.984 AC: 15064 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 3458 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5176 AN: 5176

South Asian (SAS) AF: 1.00 AC: 4834 AN: 4834

European-Finnish (FIN) AF: 1.00 AC: 10630 AN: 10630

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67949 AN: 68048

Other (OTH) AF: 0.974 AC: 2060 AN: 2114

Alfa AF: 0.984 Hom.: 23752

Bravo AF: 0.959

Asia WGS AF: 0.991 AC: 3446 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Microcephaly 3, primary, autosomal recessive (2)
-	-	2	not provided (2)
-	-	1	Primary Microcephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	8.2
DANN	Benign	0.48
PhyloP100		-0.076
PromoterAI		0.021	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs932974; hg19: chr9-123342275;