rs2008720

Variant names:

• chr22-18936232-G-T
• rs2008720
• NM_016335.6:c.56C>A

Your query was ambiguous. Multiple possible variants found:

• chr22-18936232-G-T
• chr22-18936232-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_016335.6(PRODH):​c.56C>A​(p.Pro19Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P19P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.75 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.293
• Publications: 32 publications found

Genes affected

PRODH (HGNC:9453): (proline dehydrogenase 1) This gene encodes a mitochondrial protein that catalyzes the first step in proline degradation. Mutations in this gene are associated with hyperprolinemia type 1 and susceptibility to schizophrenia 4 (SCZD4). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2010]

PRODH Gene-Disease associations (from GenCC):

• hyperprolinemia type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Orphanet

ENSG00000283809 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.471116E-6).
• BP6: Variant 22-18936232-G-T is Benign according to our data. Variant chr22-18936232-G-T is described in ClinVar as Benign. ClinVar VariationId is 1168807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016335.6. 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
	PRODH	NM_016335.6	MANE Select	c.56C>A	p.Pro19Gln	missense	Exon 1 of 14	NP_057419.5
	PRODH	NM_001368250.2		c.-114C>A		5_prime_UTR	Exon 1 of 14	NP_001355179.2	E7EQL6
	PRODH	NM_001195226.2		c.-52+158C>A		intron	N/A	NP_001182155.2	O43272-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	ENST00000357068.11	TSL:1 MANE Select	c.56C>A	p.Pro19Gln	missense	Exon 1 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.56C>A	p.Pro19Gln	missense	Exon 2 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.-52+158C>A		intron	N/A	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes AC: 0 AN: 0 Hom.: 0 Cov.: 0

GnomAD2 exomes AF: 0.561 AC: 6075 AN: 10824 AF XY: 0.564

Gnomad AFR exome AF: 0.344

Gnomad AMR exome AF: 0.568

Gnomad ASJ exome AF: 0.558

Gnomad EAS exome AF: 0.894

Gnomad FIN exome AF: 0.492

Gnomad NFE exome AF: 0.527

Gnomad OTH exome AF: 0.551

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.750 AC: 6 AN: 8 Hom.: 2 Cov.: 0 AF XY: 1.00 AC XY: 4 AN XY: 4

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

Alfa AF: 0.604 Hom.: 4772

TwinsUK AF: 0.451 AC: 1672

ALSPAC AF: 0.465 AC: 1791

ExAC AF: 0.407 AC: 5137

Asia WGS AF: 0.668 AC: 2173 AN: 3254

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Proline dehydrogenase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.8
DANN	Benign	0.89
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0000085	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.29
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.0050
Sift	Benign	0.37	T
Sift4G	Uncertain	0.043	D
Vest4		0.088
MPC		0.39
ClinPred		0.0021	T
GERP RS		-0.024
PromoterAI		-0.050	Neutral
gMVP		0.51
Mutation Taster		=161/139	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2008720; hg19: chr22-18923745; COSMIC: COSV61838822; COSMIC: COSV61838822;