Genetic Variant CRPPA:p.Pro65Ser (chr7-16421130-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001101426.4(CRPPA):c.193C>T(p.Pro65Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P65T) 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

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.65

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101426.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRPPA	NM_001101426.4	MANE Select	c.193C>T	p.Pro65Ser	missense	Exon 1 of 10	NP_001094896.1	A4D126-1
CRPPA	NM_001368197.1		c.193C>T	p.Pro65Ser	missense	Exon 1 of 9	NP_001355126.1
CRPPA	NM_001101417.4		c.193C>T	p.Pro65Ser	missense	Exon 1 of 9	NP_001094887.1	A0A140VJM1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.193C>T	p.Pro65Ser	missense	Exon 1 of 10	ENSP00000385478.2	A4D126-1
CRPPA	ENST00000399310.3	TSL:1	c.193C>T	p.Pro65Ser	missense	Exon 1 of 9	ENSP00000382249.3	A4D126-2
CRPPA	ENST00000856526.1		c.193C>T	p.Pro65Ser	missense	Exon 1 of 8	ENSP00000526585.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1175846

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

566854

African (AFR)

AF:

0.00

AC:

AN:

23794

American (AMR)

AF:

0.00

AC:

AN:

10112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16108

East Asian (EAS)

AF:

0.00

AC:

AN:

27050

South Asian (SAS)

AF:

0.00

AC:

AN:

41356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40920

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4782

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

964476

Other (OTH)

AF:

0.00

AC:

AN:

47248

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

2.9

PhyloP100

6.6

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.83

Sift

Benign

0.041

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.64

MutPred

0.79

Loss of phosphorylation at T64 (P = 0.0997)

MVP

0.67

MPC

0.35

ClinPred

0.99

GERP RS

4.2

PromoterAI

-0.15

Neutral

(source)

Varity_R

0.77

gMVP

0.77

Mutation Taster

=36/64

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over