rs114363936

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001101426.4(CRPPA):​c.947C>A​(p.Thr316Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,609,120 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 12 hom., cov: 33)
Exomes 𝑓: 0.00064 ( 12 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

1
17

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.210
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-AS1 (HGNC:48962): (CRPPA antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.008729011).
BP6
Variant 7-16258999-G-T is Benign according to our data. Variant chr7-16258999-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 198454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-16258999-G-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00653 (993/152088) while in subpopulation AFR AF= 0.0225 (936/41518). AF 95% confidence interval is 0.0213. There are 12 homozygotes in gnomad4. There are 459 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CRPPANM_001101426.4 linkuse as main transcriptc.947C>A p.Thr316Lys missense_variant 7/10 ENST00000407010.7 NP_001094896.1
CRPPA-AS1NR_038947.1 linkuse as main transcriptn.241-7228G>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CRPPAENST00000407010.7 linkuse as main transcriptc.947C>A p.Thr316Lys missense_variant 7/105 NM_001101426.4 ENSP00000385478 P1A4D126-1
CRPPA-AS1ENST00000438573.5 linkuse as main transcriptn.222-2900G>T intron_variant, non_coding_transcript_variant 1

Frequencies

GnomAD3 genomes
AF:
0.00653
AC:
993
AN:
151970
Hom.:
12
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0226
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00230
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00669
GnomAD3 exomes
AF:
0.00150
AC:
367
AN:
244720
Hom.:
7
AF XY:
0.00115
AC XY:
153
AN XY:
132704
show subpopulations
Gnomad AFR exome
AF:
0.0201
Gnomad AMR exome
AF:
0.00133
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000670
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000811
Gnomad OTH exome
AF:
0.00102
GnomAD4 exome
AF:
0.000640
AC:
932
AN:
1457032
Hom.:
12
Cov.:
29
AF XY:
0.000553
AC XY:
401
AN XY:
724740
show subpopulations
Gnomad4 AFR exome
AF:
0.0214
Gnomad4 AMR exome
AF:
0.00150
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000584
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000343
Gnomad4 OTH exome
AF:
0.00166
GnomAD4 genome
AF:
0.00653
AC:
993
AN:
152088
Hom.:
12
Cov.:
33
AF XY:
0.00617
AC XY:
459
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.0225
Gnomad4 AMR
AF:
0.00229
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00662
Alfa
AF:
0.000674
Hom.:
0
Bravo
AF:
0.00757
ESP6500AA
AF:
0.0197
AC:
76
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00185
AC:
223
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000120

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 26, 2015- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 14, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:3
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2023CRPPA: BP4, BS1, BS2 -
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 01, 2021- -
Congenital Muscular Dystrophy, alpha-dystroglycan related Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
16
DANN
Benign
0.92
DEOGEN2
Benign
0.0072
T;.
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.53
D
LIST_S2
Benign
0.47
T;T
MetaRNN
Benign
0.0087
T;T
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
1.8
L;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.2
N;N
REVEL
Benign
0.28
Sift
Uncertain
0.014
D;D
Sift4G
Benign
0.57
T;T
Polyphen
0.87
P;.
Vest4
0.40
MVP
0.50
MPC
0.067
ClinPred
0.0067
T
GERP RS
0.23
Varity_R
0.14
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
Details are displayed if max score is > 0.2

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: rs114363936; hg19: chr7-16298624; COSMIC: COSV99063057; API