chr1-225920500-C-T

Variant names:

• chr1-225920500-C-T
• rs73131849
• NM_013328.4:c.918G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013328.4(PYCR2):​c.918G>A​(p.Gly306Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,512,040 control chromosomes in the GnomAD database, including 22,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3368 hom., cov: 31)
  • Exomes 𝑓: 0.16 (18640 hom.)
• Consequence: PYCR2 NM_013328.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.162
• Publications: 10 publications found

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]

PYCR2 Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255835 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-225920500-C-T is Benign according to our data. Variant chr1-225920500-C-T is described in ClinVar as [Benign]. Clinvar id is 1166246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.162 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYCR2	NM_013328.4	c.918G>A	p.Gly306Gly	synonymous_variant	Exon 7 of 7	ENST00000343818.11	NP_037460.2
PYCR2	NM_001271681.2	c.696G>A	p.Gly232Gly	synonymous_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.918G>A	p.Gly306Gly	synonymous_variant	Exon 7 of 7	1	NM_013328.4	ENSP00000342502.6
ENSG00000255835	ENST00000432920.2	c.575+708G>A		intron_variant	Intron 5 of 7	2		ENSP00000414068.2
PYCR2	ENST00000612039.4	c.696G>A	p.Gly232Gly	synonymous_variant	Exon 6 of 6	3		ENSP00000478165.1
PYCR2	ENST00000478402.5	n.2527G>A		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30068 AN: 151838 Hom.: 3368 Cov.: 31

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0810

Gnomad SAS AF: 0.0630

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.174 AC: 38600 AN: 222218 AF XY: 0.163

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.0914

Gnomad FIN exome AF: 0.209

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.158 AC: 215469 AN: 1360082 Hom.: 18640 Cov.: 32 AF XY: 0.154 AC XY: 104642 AN XY: 678536

African (AFR) AF: 0.287 AC: 8636 AN: 30070

American (AMR) AF: 0.306 AC: 11540 AN: 37656

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 2776 AN: 23400

East Asian (EAS) AF: 0.0771 AC: 2984 AN: 38680

South Asian (SAS) AF: 0.0674 AC: 5410 AN: 80238

European-Finnish (FIN) AF: 0.200 AC: 10468 AN: 52398

Middle Eastern (MID) AF: 0.125 AC: 677 AN: 5428

European-Non Finnish (NFE) AF: 0.159 AC: 164154 AN: 1035618

Other (OTH) AF: 0.156 AC: 8824 AN: 56594

GnomAD4 genome AF: 0.198 AC: 30095 AN: 151958 Hom.: 3368 Cov.: 31 AF XY: 0.197 AC XY: 14648 AN XY: 74252

African (AFR) AF: 0.286 AC: 11842 AN: 41396

American (AMR) AF: 0.236 AC: 3609 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3466

East Asian (EAS) AF: 0.0808 AC: 418 AN: 5174

South Asian (SAS) AF: 0.0632 AC: 305 AN: 4824

European-Finnish (FIN) AF: 0.218 AC: 2297 AN: 10546

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10470 AN: 67970

Other (OTH) AF: 0.184 AC: 388 AN: 2110

Alfa AF: 0.171 Hom.: 953

Bravo AF: 0.208

Asia WGS AF: 0.0750 AC: 263 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.2
DANN	Benign	0.66
PhyloP100		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73131849; hg19: chr1-226108200; COSMIC: COSV59524610; COSMIC: COSV59524610;