rs202108204

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001101426.4(CRPPA):c.532G>A(p.Gly178Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,612,486 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predicting alterations to normal splicing. 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. G178A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CRPPA
NM_001101426.4 missense, splice_region

Scores

Splicing: ADA: 0.9602

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 7.57

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CRPPA	NM_001101426.4 linkuse as main transcript	c.532G>A	p.Gly178Arg	missense_variant, splice_region_variant	2/10	ENST00000407010.7
CRPPA	NM_001368197.1 linkuse as main transcript	c.532G>A	p.Gly178Arg	missense_variant, splice_region_variant	2/9
CRPPA	NM_001101417.4 linkuse as main transcript	c.532G>A	p.Gly178Arg	missense_variant, splice_region_variant	2/9
CRPPA	NR_160656.1 linkuse as main transcript	n.748G>A		splice_region_variant, non_coding_transcript_exon_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7 linkuse as main transcript	c.532G>A	p.Gly178Arg	missense_variant, splice_region_variant	2/10	5	NM_001101426.4	P1	A4D126-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000174

AC:

AN:

246702

Hom.:

AF XY:

0.000149

AC XY:

AN XY:

133794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000899

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000296

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000160

AC:

233

AN:

1460174

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

124

AN XY:

726102

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00111

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000173

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000118

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000325

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 10, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30564623) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 01, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.532G>A (p.G178R) alteration is located in exon 2 (coding exon 2) of the ISPD gene. This alteration results from a G to A substitution at nucleotide position 532, causing the glycine (G) at amino acid position 178 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2022

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 178 of the ISPD protein (p.Gly178Arg). This variant is present in population databases (rs202108204, gnomAD 0.08%). 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: 282161). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

Congenital Muscular Dystrophy, alpha-dystroglycan related

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.40

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

3.0

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Pathogenic

0.74

Sift

Benign

0.047

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

1.0

D;.

Vest4

0.92

MutPred

0.49

Loss of catalytic residue at G178 (P = 0.0356);Loss of catalytic residue at G178 (P = 0.0356);

MVP

0.80

MPC

0.38

ClinPred

0.59

GERP RS

5.9

Varity_R

0.94

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.80

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over