1-225920494-G-C

Position:

• chr1-225920494-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_013328.4(PYCR2):​c.924C>G​(p.Leu308=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000586 in 1,497,182 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00055 (6 hom.)
• Consequence: PYCR2 NM_013328.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.373

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-225920494-G-C is Benign according to our data. Variant chr1-225920494-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 770123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.373 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000913 (139/152274) while in subpopulation EAS AF= 0.00907 (47/5184). AF 95% confidence interval is 0.00701. There are 1 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYCR2	NM_013328.4	c.924C>G	p.Leu308=	synonymous_variant	7/7	ENST00000343818.11	NP_037460.2
PYCR2	NM_001271681.2	c.702C>G	p.Leu234=	synonymous_variant	6/6		NP_001258610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYCR2	ENST00000343818.11	c.924C>G	p.Leu308=	synonymous_variant	7/7	1	NM_013328.4	ENSP00000342502	P1
PYCR2	ENST00000612039.4	c.702C>G	p.Leu234=	synonymous_variant	6/6	3		ENSP00000478165
PYCR2	ENST00000478402.5	n.2533C>G		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152156 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00905

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00231 AC: 492 AN: 212966 Hom.: 4 AF XY: 0.00193 AC XY: 222 AN XY: 115054

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00839

Gnomad SAS exome AF: 0.000842

Gnomad FIN exome AF: 0.000102

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000549 AC: 739 AN: 1344908 Hom.: 6 Cov.: 31 AF XY: 0.000518 AC XY: 347 AN XY: 670230

Gnomad4 AFR exome AF: 0.000169

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00421

Gnomad4 SAS exome AF: 0.000894

Gnomad4 FIN exome AF: 0.0000384

Gnomad4 NFE exome AF: 0.0000711

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000913 AC: 139 AN: 152274 Hom.: 1 Cov.: 31 AF XY: 0.000980 AC XY: 73 AN XY: 74456

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00907

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000538 Hom.: 0

Bravo AF: 0.00135

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	PYCR2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 06, 2018

- -

Hypomyelinating leukodystrophy 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.7
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs181648767; hg19: chr1-226108194;