1-225921311-A-G

Variant names:

• chr1-225921311-A-G
• NM_013328.4:c.694T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_013328.4(PYCR2):​c.694T>C​(p.Cys232Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,433,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 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. C232G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PYCR2 NM_013328.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.25

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-225921311-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 254250.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYCR2	NM_013328.4	c.694T>C	p.Cys232Arg	missense_variant	Exon 6 of 7	ENST00000343818.11	NP_037460.2
PYCR2	NM_001271681.2	c.472T>C	p.Cys158Arg	missense_variant	Exon 5 of 6		NP_001258610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYCR2	ENST00000343818.11	c.694T>C	p.Cys232Arg	missense_variant	Exon 6 of 7	1	NM_013328.4	ENSP00000342502.6
ENSG00000255835	ENST00000432920.2	c.472T>C	p.Cys158Arg	missense_variant	Exon 5 of 8	2		ENSP00000414068.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1433476 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 2 AN XY: 714542

Gnomad4 AFR exome AF: 0.00

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T;.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;T;D;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.6	.;.;.;H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.4	D;.;.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.92	.;.;.;P
Vest4		0.91
MutPred		0.74		.;.;.;Gain of disorder (P = 0.0132);
MVP		0.93
MPC		1.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.98
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-226109011;