rs61734789

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001101426.4(CRPPA):c.407C>T(p.Ala136Val) variant causes a missense change. The variant allele was found at a frequency of 0.0365 in 1,613,930 control chromosomes in the GnomAD database, including 1,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A136A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.024 ( 59 hom., cov: 33)

Exomes 𝑓: 0.038 ( 1274 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.21

Publications

12 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010987341).

BP6

Variant 7-16406188-G-A is Benign according to our data. Variant chr7-16406188-G-A is described in ClinVar as Benign. ClinVar VariationId is 129287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.024 (3654/152308) while in subpopulation NFE AF = 0.0381 (2594/68026). AF 95% confidence interval is 0.0369. There are 59 homozygotes in GnomAd4. There are 1700 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CRPPA	NM_001101426.4 link	c.407C>T	p.Ala136Val	missense_variant	Exon 2 of 10	ENST00000407010.7	NP_001094896.1
CRPPA	NM_001368197.1 link	c.407C>T	p.Ala136Val	missense_variant	Exon 2 of 9		NP_001355126.1
CRPPA	NM_001101417.4 link	c.407C>T	p.Ala136Val	missense_variant	Exon 2 of 9		NP_001094887.1
CRPPA	NR_160656.1 link	n.623C>T		non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7 link	c.407C>T	p.Ala136Val	missense_variant	Exon 2 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes

AF:

0.0240

AC:

3657

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00849

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.0190

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00869

Gnomad FIN

AF:

0.0236

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0382

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0232

AC:

5776

AN:

249146

AF XY:

0.0239

show subpopulations

Gnomad AFR exome

AF:

0.00775

Gnomad AMR exome

AF:

0.00864

Gnomad ASJ exome

AF:

0.00368

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0251

Gnomad NFE exome

AF:

0.0377

Gnomad OTH exome

AF:

0.0238

GnomAD4 exome

AF:

0.0378

AC:

55266

AN:

1461622

Hom.:

1274

Cov.:

AF XY:

0.0367

AC XY:

26681

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.00612

AC:

205

AN:

33480

American (AMR)

AF:

0.00899

AC:

402

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00421

AC:

110

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0128

AC:

1106

AN:

86258

European-Finnish (FIN)

AF:

0.0246

AC:

1312

AN:

53400

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0451

AC:

50120

AN:

1111800

Other (OTH)

AF:

0.0330

AC:

1991

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

2919

5838

8758

11677

14596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1932

3864

5796

7728

9660

<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:

0.0240

AC:

3654

AN:

152308

Hom.:

Cov.:

AF XY:

0.0228

AC XY:

1700

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00847

AC:

352

AN:

41576

American (AMR)

AF:

0.0190

AC:

291

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00849

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0236

AC:

250

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0381

AC:

2594

AN:

68026

Other (OTH)

AF:

0.0265

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

193

387

580

774

967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0331

Hom.:

347

Bravo

AF:

0.0231

ESP6500AA

AF:

0.00937

AC:

ESP6500EA

AF:

0.0352

AC:

290

ExAC

AF:

0.0241

AC:

2909

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0329

EpiControl

AF:

0.0350

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Oct 20, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala136Val in exon 2 of ISPD: This variant is not expected to have clinical sig nificance because it has been identified in 3.5% (290/8230) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs61734789).

Feb 23, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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.

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital Muscular Dystrophy, alpha-dystroglycan related

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 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

0.093

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

T;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

2.0

M;M

PhyloP100

4.2

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.11

T;T

Sift4G

Benign

0.23

T;T

Vest4

0.081

ClinPred

0.013

GERP RS

5.9

Varity_R

0.15

gMVP

0.66

Mutation Taster

=92/8

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over