1-225921199-T-G

Variant names:

• chr1-225921199-T-G
• rs41307726
• NM_013328.4:c.797+9A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013328.4(PYCR2):​c.797+9A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,609,918 control chromosomes in the GnomAD database, including 9,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (637 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8377 hom.)
• Consequence: PYCR2 NM_013328.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.07
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-225921199-T-G is Benign according to our data. Variant chr1-225921199-T-G is described in ClinVar as Benign. ClinVar VariationId is 1167877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

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.797+9A>C		intron	N/A	NP_037460.2
	PYCR2	NM_001271681.2		c.575+9A>C		intron	N/A	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.797+9A>C		intron	N/A	ENSP00000342502.6	Q96C36
	ENSG00000255835	ENST00000432920.2	TSL:2	c.575+9A>C		intron	N/A	ENSP00000414068.2	J3KR12
	PYCR2	ENST00000872062.1		c.794+9A>C		intron	N/A	ENSP00000542121.1

Frequencies

GnomAD3 genomes AF: 0.0806 AC: 12252 AN: 152090 Hom.: 637 Cov.: 32

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.0386

Gnomad AMR AF: 0.0714

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.0597

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0866

GnomAD2 exomes AF: 0.100 AC: 24801 AN: 247846 AF XY: 0.107

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.0474

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.0586

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.0980

GnomAD4 exome AF: 0.102 AC: 149366 AN: 1457710 Hom.: 8377 Cov.: 32 AF XY: 0.105 AC XY: 76380 AN XY: 725048

African (AFR) AF: 0.0148 AC: 495 AN: 33394

American (AMR) AF: 0.0492 AC: 2182 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 3872 AN: 25826

East Asian (EAS) AF: 0.0567 AC: 2249 AN: 39658

South Asian (SAS) AF: 0.151 AC: 12950 AN: 85814

European-Finnish (FIN) AF: 0.129 AC: 6873 AN: 53310

Middle Eastern (MID) AF: 0.125 AC: 713 AN: 5722

European-Non Finnish (NFE) AF: 0.103 AC: 113995 AN: 1109466

Other (OTH) AF: 0.100 AC: 6037 AN: 60202

GnomAD4 genome AF: 0.0805 AC: 12251 AN: 152208 Hom.: 637 Cov.: 32 AF XY: 0.0821 AC XY: 6107 AN XY: 74428

African (AFR) AF: 0.0192 AC: 796 AN: 41562

American (AMR) AF: 0.0713 AC: 1091 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 545 AN: 3470

East Asian (EAS) AF: 0.0598 AC: 309 AN: 5168

South Asian (SAS) AF: 0.140 AC: 675 AN: 4818

European-Finnish (FIN) AF: 0.128 AC: 1358 AN: 10594

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7226 AN: 67982

Other (OTH) AF: 0.0862 AC: 182 AN: 2112

Alfa AF: 0.0867 Hom.: 605

Bravo AF: 0.0712

Asia WGS AF: 0.0880 AC: 307 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.111

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.60
DANN	Benign	0.53
PhyloP100		-1.1
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: rs41307726; hg19: chr1-226108899; COSMIC: COSV107415090; COSMIC: COSV107415090;