Genetic Variant CRPPA:p.Pro5Thr (chr7-16421310-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001101426.4(CRPPA):c.13C>A(p.Pro5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. P5S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.54

Publications

0 publications found

Variant links:

Genes affected

CRPPA (HGNC:37276): (CDP-L-ribitol pyrophosphorylase A) This gene encodes a 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase-like protein. Mutations in this gene are the cause of Walker-Warburg syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

CRPPA Gene-Disease associations (from GenCC):

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
myopathy caused by variation in CRPPA
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2U
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy without intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscular dystrophy-dystroglycanopathy, type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CRPPA links:

ENSG00000272537 (HGNC:):

ENSG00000272537 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09449318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRPPA	NM_001101426.4 link	c.13C>A	p.Pro5Thr	missense_variant	Exon 1 of 10	ENST00000407010.7	NP_001094896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7 link	c.13C>A	p.Pro5Thr	missense_variant	Exon 1 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1108240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

526700

African (AFR)

AF:

0.00

AC:

AN:

22792

American (AMR)

AF:

0.00

AC:

AN:

8294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14584

East Asian (EAS)

AF:

0.00

AC:

AN:

26312

South Asian (SAS)

AF:

0.00

AC:

AN:

26376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2956

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

930626

Other (OTH)

AF:

0.00

AC:

AN:

44286

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0077

T;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.51

T;T

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.094

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.0

N;N

PhyloP100

1.5

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.036

D;D

Polyphen

0.0010

B;.

Vest4

0.16

MutPred

0.26

Gain of phosphorylation at P5 (P = 0.0031);Gain of phosphorylation at P5 (P = 0.0031);

MVP

0.21

MPC

0.073

ClinPred

0.12

GERP RS

-0.18

PromoterAI

-0.23

Neutral

(source)

Varity_R

0.081

gMVP

0.27

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over