12-62508398-C-A

Variant names:

• chr12-62508398-C-A
• rs2071216408
• NM_015026.3:c.902C>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_015026.3(MON2):​c.902C>A​(p.Pro301Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MON2 NM_015026.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.78

Genes affected

MON2 (HGNC:29177): (MON2 homolog, regulator of endosome-to-Golgi trafficking) Predicted to be involved in Golgi to endosome transport. Located in early endosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MON2	NM_015026.3	c.902C>A	p.Pro301Gln	missense_variant	Exon 8 of 35	ENST00000393630.8	NP_055841.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MON2	ENST00000393630.8	c.902C>A	p.Pro301Gln	missense_variant	Exon 8 of 35	1	NM_015026.3	ENSP00000377250.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727186

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.902C>A (p.P301Q) alteration is located in exon 8 (coding exon 8) of the MON2 gene. This alteration results from a C to A substitution at nucleotide position 902, causing the proline (P) at amino acid position 301 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;T;.;.;.;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.4	.;L;L;L;L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.0	.;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	.;D;D;D;D;D
Sift4G	Uncertain	0.0080	.;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.
Vest4		0.69, 0.68, 0.81, 0.63, 0.60
MutPred		0.25		Loss of glycosylation at P301 (P = 0.0266);Loss of glycosylation at P301 (P = 0.0266);Loss of glycosylation at P301 (P = 0.0266);Loss of glycosylation at P301 (P = 0.0266);Loss of glycosylation at P301 (P = 0.0266);Loss of glycosylation at P301 (P = 0.0266);
MVP		0.22
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.55
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs2071216408; hg19: chr12-62902178;