6-89146440-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001010853.3(PM20D2):c.296C>G(p.Pro99Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000875 in 1,370,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000088 (0 hom.)
• Consequence: PM20D2 NM_001010853.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.323

Genes affected

PM20D2 (HGNC:21408): (peptidase M20 domain containing 2) Enables dipeptidase activity and identical protein binding activity. Acts upstream of or within proteolysis and regulation of cellular protein metabolic process. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LOC101929004 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070159405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PM20D2	NM_001010853.3	c.296C>G	p.Pro99Arg	missense_variant	1/7	ENST00000275072.5
LOC101929004	XR_942766.4	n.427G>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PM20D2	ENST00000275072.5	c.296C>G	p.Pro99Arg	missense_variant	1/7	1	NM_001010853.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000875 AC: 12 AN: 1370738 Hom.: 0 Cov.: 31 AF XY: 0.0000133 AC XY: 9 AN XY: 676150

Gnomad4 AFR exome AF: 0.000239

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: 0.00000372

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.296C>G (p.P99R) alteration is located in exon 1 (coding exon 1) of the PM20D2 gene. This alteration results from a C to G substitution at nucleotide position 296, causing the proline (P) at amino acid position 99 to be replaced by an arginine (R). 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	Benign	0.084
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	2.4
Dann	Benign	0.29
DEOGEN2	Benign	0.0093	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.076
Sift	Benign	0.67	T
Sift4G	Benign	0.43	T
Polyphen		0.0090	B
Vest4		0.40
MutPred		0.39		Gain of methylation at P99 (P = 0.0311);
MVP		0.14
MPC		0.96
ClinPred		0.029	T
GERP RS		-0.084
Varity_R		0.023
gMVP		0.45

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: rs543551303; hg19: chr6-89856159;