4-121816718-A-G

Variant names:

• chr4-121816718-A-G
• rs1507987
• NM_001237.5:c.*920T>C

Variant summary

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

The NM_001237.5(CCNA2):​c.*920T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,496,656 control chromosomes in the GnomAD database, including 2,234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (875 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1359 hom.)
• Consequence: CCNA2 NM_001237.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.997
• Publications: 6 publications found

Genes affected

CCNA2 (HGNC:1578): (cyclin A2) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members function as regulators of the cell cycle. This protein binds and activates cyclin-dependent kinase 2 and thus promotes transition through G1/S and G2/M. [provided by RefSeq, Aug 2016]

EXOSC9 (HGNC:9137): (exosome component 9) This gene encodes a component of the human exosome, a exoribonuclease complex which processes and degrades RNA in the nucleus and cytoplasm. This component may play a role in mRNA degradation and the polymyositis/scleroderma autoantigen complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

EXOSC9 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia, type 1D

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-121816718-A-G is Benign according to our data. Variant chr4-121816718-A-G is described in ClinVar as Benign. ClinVar VariationId is 1229339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001237.5. 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
	CCNA2	NM_001237.5	MANE Select	c.*920T>C		3_prime_UTR	Exon 8 of 8	NP_001228.2	P20248
	EXOSC9	NM_005033.3	MANE Select	c.1236-54A>G		intron	N/A	NP_005024.2	Q06265-1
	EXOSC9	NM_001034194.2		c.1287-54A>G		intron	N/A	NP_001029366.1	Q06265-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCNA2	ENST00000274026.10	TSL:1 MANE Select	c.*920T>C		3_prime_UTR	Exon 8 of 8	ENSP00000274026.5	P20248
	EXOSC9	ENST00000243498.10	TSL:1 MANE Select	c.1236-54A>G		intron	N/A	ENSP00000243498.5	Q06265-1
	EXOSC9	ENST00000379663.7	TSL:1	c.1287-54A>G		intron	N/A	ENSP00000368984.3	Q06265-2

Frequencies

GnomAD3 genomes AF: 0.0654 AC: 9952 AN: 152140 Hom.: 874 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.0440

GnomAD4 exome AF: 0.0149 AC: 20010 AN: 1344398 Hom.: 1359 Cov.: 28 AF XY: 0.0156 AC XY: 10363 AN XY: 664166

African (AFR) AF: 0.194 AC: 5465 AN: 28190

American (AMR) AF: 0.0139 AC: 305 AN: 21928

Ashkenazi Jewish (ASJ) AF: 0.000403 AC: 9 AN: 22332

East Asian (EAS) AF: 0.154 AC: 5501 AN: 35792

South Asian (SAS) AF: 0.0671 AC: 4634 AN: 69110

European-Finnish (FIN) AF: 0.00579 AC: 281 AN: 48522

Middle Eastern (MID) AF: 0.0153 AC: 82 AN: 5350

European-Non Finnish (NFE) AF: 0.00192 AC: 2030 AN: 1057766

Other (OTH) AF: 0.0307 AC: 1703 AN: 55408

GnomAD4 genome AF: 0.0655 AC: 9972 AN: 152258 Hom.: 875 Cov.: 32 AF XY: 0.0671 AC XY: 4994 AN XY: 74460

African (AFR) AF: 0.189 AC: 7834 AN: 41512

American (AMR) AF: 0.0245 AC: 375 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.194 AC: 1007 AN: 5182

South Asian (SAS) AF: 0.0831 AC: 401 AN: 4828

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00278 AC: 189 AN: 68028

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0366 Hom.: 113

Bravo AF: 0.0723

Asia WGS AF: 0.147 AC: 509 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.0
DANN	Benign	0.68
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs1507987; hg19: chr4-122737873; COSMIC: COSV54666252; COSMIC: COSV54666252;