NM_018249.6:c.-3G>T

Variant names:

• chr9-120579981-C-A
• rs932975
• NM_018249.6:c.-3G>T

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.-3G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,607,410 control chromosomes in the GnomAD database, including 796,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73013 hom., cov: 36)
  • Exomes 𝑓: 1.0 (723320 hom.)
• Consequence: CDK5RAP2 NM_018249.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.357
• 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=-0.92).
• BP6: Variant 9-120579981-C-A is Benign according to our data. Variant chr9-120579981-C-A is described in ClinVar as Benign. ClinVar VariationId is 95896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.-3G>T		5_prime_UTR	Exon 1 of 38	NP_060719.4
	CDK5RAP2	NM_001410994.1		c.-3G>T		5_prime_UTR	Exon 1 of 38	NP_001397923.1	A0A8I5QKL1
	CDK5RAP2	NM_001410993.1		c.-3G>T		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.-3G>T		5_prime_UTR	Exon 1 of 38	ENSP00000343818.4	Q96SN8-1
	CDK5RAP2	ENST00000360190.8	TSL:1	c.-3G>T		5_prime_UTR	Exon 1 of 37	ENSP00000353317.4	Q96SN8-4
	CDK5RAP2	ENST00000473282.6	TSL:1	n.-3G>T		non_coding_transcript_exon	Exon 1 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes AF: 0.979 AC: 148989 AN: 152236 Hom.: 72971 Cov.: 36

Gnomad AFR AF: 0.929

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.989

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: 0.984

GnomAD2 exomes AF: 0.993 AC: 247017 AN: 248680 AF XY: 0.995

Gnomad AFR exome AF: 0.924

Gnomad AMR exome AF: 0.994

Gnomad ASJ exome AF: 0.997

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.997 AC: 1450731 AN: 1455056 Hom.: 723320 Cov.: 30 AF XY: 0.997 AC XY: 722460 AN XY: 724426

African (AFR) AF: 0.926 AC: 30853 AN: 33336

American (AMR) AF: 0.993 AC: 44395 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 26018 AN: 26082

East Asian (EAS) AF: 1.00 AC: 39663 AN: 39664

South Asian (SAS) AF: 1.00 AC: 86068 AN: 86084

European-Finnish (FIN) AF: 1.00 AC: 53354 AN: 53354

Middle Eastern (MID) AF: 0.985 AC: 5668 AN: 5756

European-Non Finnish (NFE) AF: 0.999 AC: 1104967 AN: 1105966

Other (OTH) AF: 0.994 AC: 59745 AN: 60126

GnomAD4 genome AF: 0.979 AC: 149089 AN: 152354 Hom.: 73013 Cov.: 36 AF XY: 0.979 AC XY: 72947 AN XY: 74508

African (AFR) AF: 0.928 AC: 38594 AN: 41568

American (AMR) AF: 0.989 AC: 15147 AN: 15310

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

East Asian (EAS) AF: 1.00 AC: 5178 AN: 5178

South Asian (SAS) AF: 1.00 AC: 4832 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

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

European-Non Finnish (NFE) AF: 0.999 AC: 67972 AN: 68046

Other (OTH) AF: 0.984 AC: 2081 AN: 2114

Alfa AF: 0.990 Hom.: 36761

Bravo AF: 0.975

Asia WGS AF: 0.993 AC: 3455 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.998

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	-0.92
CADD	Benign	5.3
DANN	Benign	0.63
PhyloP100		0.36
PromoterAI		-0.14	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: rs932975; hg19: chr9-123342259;