chr1-225920564-G-T

Variant names:

• chr1-225920564-G-T
• rs1671809392
• NM_013328.4:c.854C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_013328.4(PYCR2):​c.854C>A​(p.Thr285Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T285I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PYCR2 NM_013328.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.59
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.94826 (below the threshold of 3.09). Trascript score misZ: 0.76229 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive primary microcephaly, hypomyelinating leukodystrophy 10.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYCR2	NM_013328.4	c.854C>A	p.Thr285Asn	missense_variant	Exon 7 of 7	ENST00000343818.11	NP_037460.2
PYCR2	NM_001271681.2	c.632C>A	p.Thr211Asn	missense_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.854C>A	p.Thr285Asn	missense_variant	Exon 7 of 7	1	NM_013328.4	ENSP00000342502.6
ENSG00000255835	ENST00000432920.2	c.575+644C>A		intron_variant	Intron 5 of 7	2		ENSP00000414068.2
PYCR2	ENST00000612039.4	c.632C>A	p.Thr211Asn	missense_variant	Exon 6 of 6	3		ENSP00000478165.1
PYCR2	ENST00000478402.5	n.2463C>A		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.2	.;.;M
PhyloP100		9.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.68	.;.;N
REVEL	Benign	0.27
Sift	Uncertain	0.0030	.;.;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.99	.;.;D
Vest4		0.68
MutPred		0.12		.;.;Gain of ubiquitination at K284 (P = 0.0701);
MVP		0.95
MPC		1.0
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.38
gMVP		0.84
Mutation Taster		=23/77	disease causing

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: rs1671809392; hg19: chr1-226108264; COSMIC: COSV100661472; COSMIC: COSV100661472;