rs181648767

Variant names:

• chr1-225920494-G-C
• rs181648767
• NM_013328.4:c.924C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-225920494-G-C
• chr1-225920494-G-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_013328.4(PYCR2):​c.924C>G​(p.Leu308Leu) 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
• Publications: 1 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: Illumina, G2P, 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=-0.66).
• BP6: Variant 1-225920494-G-C is Benign according to our data. Variant chr1-225920494-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013328.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYCR2	NM_013328.4	MANE Select	c.924C>G	p.Leu308Leu	synonymous	Exon 7 of 7	NP_037460.2
	PYCR2	NM_001271681.2		c.702C>G	p.Leu234Leu	synonymous	Exon 6 of 6	NP_001258610.1	A0A087WTV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYCR2	ENST00000343818.11	TSL:1 MANE Select	c.924C>G	p.Leu308Leu	synonymous	Exon 7 of 7	ENSP00000342502.6	Q96C36
	ENSG00000255835	ENST00000432920.2	TSL:2	c.575+714C>G		intron	N/A	ENSP00000414068.2	J3KR12
	PYCR2	ENST00000872062.1		c.921C>G	p.Leu307Leu	synonymous	Exon 7 of 7	ENSP00000542121.1

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

GnomAD2 exomes AF: 0.00231 AC: 492 AN: 212966 AF XY: 0.00193

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 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

African (AFR) AF: 0.000169 AC: 5 AN: 29572

American (AMR) AF: 0.0102 AC: 367 AN: 35914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22678

East Asian (EAS) AF: 0.00421 AC: 162 AN: 38500

South Asian (SAS) AF: 0.000894 AC: 70 AN: 78258

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52016

Middle Eastern (MID) AF: 0.000374 AC: 2 AN: 5346

European-Non Finnish (NFE) AF: 0.0000711 AC: 73 AN: 1026572

Other (OTH) AF: 0.00103 AC: 58 AN: 56052

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

African (AFR) AF: 0.000168 AC: 7 AN: 41548

American (AMR) AF: 0.00471 AC: 72 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00907 AC: 47 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000538 Hom.: 0

Bravo AF: 0.00135

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hypomyelinating leukodystrophy 10 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.7
DANN	Benign	0.67
PhyloP100		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs181648767; hg19: chr1-226108194;