chr1-225920597-T-C

Variant names:

• chr1-225920597-T-C
• NM_013328.4:c.821A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_013328.4(PYCR2):​c.821A>G​(p.Gln274Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PYCR2 NM_013328.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66

Genes affected

PYCR2 (HGNC:30262): (pyrroline-5-carboxylate reductase 2) This gene belongs to the pyrroline-5-carboxylate reductase family. The encoded mitochondrial protein catalyzes the conversion of pyrroline-5-carboxylate to proline, which is the last step in proline biosynthesis. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Nov 2012]

ENSG00000255835 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.94826 (below the threshold of 3.09). Trascript score misZ: 0.76229 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive primary microcephaly, hypomyelinating leukodystrophy 10.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26568264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYCR2	NM_013328.4	c.821A>G	p.Gln274Arg	missense_variant	Exon 7 of 7	ENST00000343818.11	NP_037460.2
PYCR2	NM_001271681.2	c.599A>G	p.Gln200Arg	missense_variant	Exon 6 of 6		NP_001258610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYCR2	ENST00000343818.11	c.821A>G	p.Gln274Arg	missense_variant	Exon 7 of 7	1	NM_013328.4	ENSP00000342502.6
ENSG00000255835	ENST00000432920.2	c.575+611A>G		intron_variant	Intron 5 of 7	2		ENSP00000414068.2
PYCR2	ENST00000612039.4	c.599A>G	p.Gln200Arg	missense_variant	Exon 6 of 6	3		ENSP00000478165.1
PYCR2	ENST00000478402.5	n.2430A>G		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.821A>G (p.Q274R) alteration is located in exon 7 (coding exon 7) of the PYCR2 gene. This alteration results from a A to G substitution at nucleotide position 821, causing the glutamine (Q) at amino acid position 274 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	0.073
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T;.;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.2	.;.;M
PhyloP100		7.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.93	.;.;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.013	.;.;D
Sift4G	Benign	0.061	T;D;D
Polyphen		0.022	.;.;B
Vest4		0.42
MutPred		0.19		.;.;Gain of helix (P = 0.0325);
MVP		0.77
MPC		0.32
ClinPred		0.88	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.20
gMVP		0.58
Mutation Taster		=74/26	polymorphism

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

hg19: chr1-226108297;