rs368593151

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001101426.4(CRPPA):​c.802C>T​(p.Arg268Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000174 in 1,612,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CRPPA
NM_001101426.4 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.96
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-16301454-G-A is Pathogenic according to our data. Variant chr7-16301454-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-16301454-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CRPPANM_001101426.4 linkuse as main transcriptc.802C>T p.Arg268Ter stop_gained 5/10 ENST00000407010.7
CRPPANM_001368197.1 linkuse as main transcriptc.697C>T p.Arg233Ter stop_gained 4/9
CRPPANM_001101417.4 linkuse as main transcriptc.652C>T p.Arg218Ter stop_gained 4/9
CRPPANR_160656.1 linkuse as main transcriptn.901-23228C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CRPPAENST00000407010.7 linkuse as main transcriptc.802C>T p.Arg268Ter stop_gained 5/105 NM_001101426.4 P1A4D126-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152122
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
247882
Hom.:
0
AF XY:
0.00000744
AC XY:
1
AN XY:
134402
show subpopulations
Gnomad AFR exome
AF:
0.0000649
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1459950
Hom.:
0
Cov.:
29
AF XY:
0.0000110
AC XY:
8
AN XY:
726202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152122
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000122
AC:
1
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 04, 2018The R268X nonsense variant in the ISPD gene has been reported previously in an individual with muscle-eye-brain disease who had a second variant identified on the opposite ISPD allele (in trans) (Roscioli et al., 2012). The R268X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 01, 2018- -
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2012- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
48
DANN
Uncertain
1.0
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Uncertain
0.94
D
MutationTaster
Benign
1.0
A;A
Vest4
0.91
GERP RS
5.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.33
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.33
Position offset: 12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368593151; hg19: chr7-16341079; API