7-16278181-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001101426.4(CRPPA):c.881A>G(p.Asp294Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,583,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.837

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08025131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CRPPA	NM_001101426.4 link	c.881A>G	p.Asp294Gly	missense_variant	Exon 6 of 10	ENST00000407010.7	NP_001094896.1
CRPPA	NM_001368197.1 link	c.776A>G	p.Asp259Gly	missense_variant	Exon 5 of 9		NP_001355126.1
CRPPA	NM_001101417.4 link	c.731A>G	p.Asp244Gly	missense_variant	Exon 5 of 9		NP_001094887.1
CRPPA	NR_160656.1 link	n.946A>G		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7 link	c.881A>G	p.Asp294Gly	missense_variant	Exon 6 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000733

AC:

AN:

232016

AF XY:

0.0000794

show subpopulations

Gnomad AFR exome

AF:

0.0000714

Gnomad AMR exome

AF:

0.0000310

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.000145

AC:

208

AN:

1431390

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

103

AN XY:

712452

show subpopulations

African (AFR)

AF:

0.0000610

AC:

AN:

32794

American (AMR)

AF:

0.0000465

AC:

AN:

42968

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25600

East Asian (EAS)

AF:

0.00

AC:

AN:

39540

South Asian (SAS)

AF:

0.00

AC:

AN:

83670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5238

European-Non Finnish (NFE)

AF:

0.000180

AC:

196

AN:

1091014

Other (OTH)

AF:

0.000135

AC:

AN:

59214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.548

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000581

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Aug 23, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U

Uncertain:1

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 294 of the ISPD protein (p.Asp294Gly). This variant is present in population databases (rs547473863, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ISPD-related conditions. ClinVar contains an entry for this variant (Variation ID: 290098). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ISPD protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.080

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.3

L;.

PhyloP100

0.84

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.25

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.024

D;D

Polyphen

0.93

P;.

Vest4

0.32

MVP

0.74

MPC

0.070

ClinPred

0.023

GERP RS

2.5

Varity_R

0.31

gMVP

0.49

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over