Genetic Variant CRPPA:p.Gly23Ser (chr7-16421256-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001101426.4(CRPPA):c.67G>A(p.Gly23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000172 in 1,162,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. G23C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.305

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27418733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRPPA	NM_001101426.4 link	c.67G>A	p.Gly23Ser	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.67G>A	p.Gly23Ser	missense_variant	Exon 1 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000172

AC:

AN:

1162552

Hom.:

Cov.:

AF XY:

0.00000179

AC XY:

AN XY:

558362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23562

American (AMR)

AF:

0.00

AC:

AN:

10392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16104

East Asian (EAS)

AF:

0.00

AC:

AN:

26862

South Asian (SAS)

AF:

0.00

AC:

AN:

38322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3646

European-Non Finnish (NFE)

AF:

0.00000209

AC:

AN:

957218

Other (OTH)

AF:

0.00

AC:

AN:

46562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0053

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.60

T;T

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.0

N;N

PhyloP100

0.30

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.64

N;N

REVEL

Benign

0.28

Sift

Uncertain

0.014

D;D

Sift4G

Benign

0.20

T;T

Polyphen

0.98

D;.

Vest4

0.055

MutPred

0.29

Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);

MVP

0.64

MPC

0.057

ClinPred

0.31

GERP RS

4.0

PromoterAI

-0.072

Neutral

(source)

Varity_R

0.13

gMVP

0.28

Mutation Taster

=93/7

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