chr20-43673807-G-C

Variant names:

• chr20-43673807-G-C
• rs1447840943
• NM_002466.4:c.22G>C

Variant summary

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

The NM_002466.4(MYBL2):​c.22G>C​(p.Glu8Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,415,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E8K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYBL2 NM_002466.4 missense, splice_region
• Scores: Splicing: ADA: 0.7493
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80
• Publications: 0 publications found

Genes affected

MYBL2 (HGNC:7548): (MYB proto-oncogene like 2) The protein encoded by this gene, a member of the MYB family of transcription factor genes, is a nuclear protein involved in cell cycle progression. The encoded protein is phosphorylated by cyclin A/cyclin-dependent kinase 2 during the S-phase of the cell cycle and possesses both activator and repressor activities. It has been shown to activate the cell division cycle 2, cyclin D1, and insulin-like growth factor-binding protein 5 genes. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2013]

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=0.23751402).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002466.4. 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
	MYBL2	NM_002466.4	MANE Select	c.22G>C	p.Glu8Gln	missense splice_region	Exon 2 of 14	NP_002457.1	P10244-1
	MYBL2	NM_001278610.2		c.22G>C	p.Glu8Gln	missense splice_region	Exon 2 of 13	NP_001265539.1	P10244-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBL2	ENST00000217026.5	TSL:1 MANE Select	c.22G>C	p.Glu8Gln	missense splice_region	Exon 2 of 14	ENSP00000217026.4	P10244-1
	MYBL2	ENST00000913824.1		c.22G>C	p.Glu8Gln	missense splice_region	Exon 2 of 15	ENSP00000583883.1
	MYBL2	ENST00000913820.1		c.22G>C	p.Glu8Gln	missense splice_region	Exon 2 of 15	ENSP00000583879.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1415164 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 699426

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32254

American (AMR) AF: 0.00 AC: 0 AN: 38034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25388

East Asian (EAS) AF: 0.00 AC: 0 AN: 37188

South Asian (SAS) AF: 0.00 AC: 0 AN: 80542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1086814

Other (OTH) AF: 0.00 AC: 0 AN: 58722

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.016	D
Polyphen		0.95	P
Vest4		0.31
MutPred		0.21		Loss of helix (P = 0.079)
MVP		0.49
MPC		2.0
ClinPred		0.90	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.24
gMVP		0.29
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.75
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1447840943; hg19: chr20-42302447;