12-62501682-C-T

Variant names:

• chr12-62501682-C-T
• rs1419366512
• NM_015026.3:c.773C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015026.3(MON2):​c.773C>T​(p.Pro258Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MON2 NM_015026.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MON2	NM_015026.3	c.773C>T	p.Pro258Leu	missense_variant	Exon 7 of 35	ENST00000393630.8	NP_055841.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MON2	ENST00000393630.8	c.773C>T	p.Pro258Leu	missense_variant	Exon 7 of 35	1	NM_015026.3	ENSP00000377250.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461802 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.773C>T (p.P258L) alteration is located in exon 7 (coding exon 7) of the MON2 gene. This alteration results from a C to T substitution at nucleotide position 773, causing the proline (P) at amino acid position 258 to be replaced by a leucine (L). 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T;.;.;.;T
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Uncertain	2.4	.;M;M;M;M;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.6	.;D;D;D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	.;D;D;D;D;D
Sift4G	Uncertain	0.013	.;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.
Vest4		0.89, 0.89, 0.90, 0.89, 0.88
MutPred		0.58		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.36
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1419366512; hg19: chr12-62895462;