rs7782939

Variant names:

Variant summary

Our verdict is The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Strong

The NM_001101426.4(CRPPA):c.55A>C (p.Ser19Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.304 (AC=394,087) in the gnomAD database across 1,297,340 control chromosomes, including 60,694 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.378. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.30 ( 6867 hom., cov: 33)

Exomes 𝑓: 0.30 ( 53827 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.69

Publications

16 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
myopathy caused by variation in CRPPA
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, 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:

ENSG00000272537 (HGNC:):

ENSG00000272537 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001101426.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (11/11 total B/LB).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3782 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001101426.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRPPA	NM_001101426.4	MANE Select	c.55A>C	p.Ser19Arg	missense	Exon 1 of 10	NP_001094896.1	A4D126-1
CRPPA	NM_001368197.1		c.55A>C	p.Ser19Arg	missense	Exon 1 of 9	NP_001355126.1
CRPPA	NM_001101417.4		c.55A>C	p.Ser19Arg	missense	Exon 1 of 9	NP_001094887.1	A0A140VJM1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.55A>C	p.Ser19Arg	missense	Exon 1 of 10	ENSP00000385478.2	A4D126-1
CRPPA	ENST00000399310.3	TSL:1	c.55A>C	p.Ser19Arg	missense	Exon 1 of 9	ENSP00000382249.3	A4D126-2
CRPPA	ENST00000856526.1		c.55A>C	p.Ser19Arg	missense	Exon 1 of 8	ENSP00000526585.1	A0ACI8QS87

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45300

AN:

151428

Hom.:

6873

Cov.:

show subpopulations

Gnomad AFR

AF:

0.294

Gnomad AMI

AF:

0.313

Gnomad AMR

AF:

0.288

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.280

Gnomad SAS

AF:

0.393

Gnomad FIN

AF:

0.300

Gnomad MID

AF:

0.271

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.278

GnomAD2 exomes

AF:

0.257

AC:

3585

AN:

13926

AF XY:

0.245

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.100

Gnomad EAS exome

AF:

0.180

Gnomad FIN exome

AF:

0.302

Gnomad NFE exome

AF:

0.172

Gnomad OTH exome

AF:

0.164

GnomAD4 exome

AF:

0.304

AC:

348776

AN:

1145802

Hom.:

53827

Cov.:

AF XY:

0.304

AC XY:

166475

AN XY:

548400

show subpopulations

African (AFR)

AF:

0.293

AC:

6839

AN:

23332

American (AMR)

AF:

0.280

AC:

2757

AN:

9850

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

3759

AN:

15656

East Asian (EAS)

AF:

0.269

AC:

7195

AN:

26774

South Asian (SAS)

AF:

0.335

AC:

11335

AN:

33788

European-Finnish (FIN)

AF:

0.292

AC:

11257

AN:

38486

Middle Eastern (MID)

AF:

0.256

AC:

859

AN:

3358

European-Non Finnish (NFE)

AF:

0.307

AC:

290780

AN:

948676

Other (OTH)

AF:

0.305

AC:

13995

AN:

45882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

13120

26240

39359

52479

65599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10972

21944

32916

43888

54860

<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:

0.299

AC:

45311

AN:

151538

Hom.:

6867

Cov.:

AF XY:

0.300

AC XY:

22202

AN XY:

74058

show subpopulations

African (AFR)

AF:

0.294

AC:

12141

AN:

41296

American (AMR)

AF:

0.288

AC:

4397

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

885

AN:

3466

East Asian (EAS)

AF:

0.280

AC:

1412

AN:

5036

South Asian (SAS)

AF:

0.393

AC:

1891

AN:

4812

European-Finnish (FIN)

AF:

0.300

AC:

3160

AN:

10528

Middle Eastern (MID)

AF:

0.274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.302

AC:

20477

AN:

67814

Other (OTH)

AF:

0.277

AC:

583

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1668

3336

5004

6672

8340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.296

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.212

AC:

7251

AN:

34150

Hom.:

1070

Local populations

ABraOM SABE-WGS-1171

AF:

0.291

AC:

682

AN:

2342

Hom.:

ChinaMAP Phase 1

AF:

0.304

Denmark Genome

AF:

0.317

AC:

AN:

300

GenomeAsia100K

AF:

0.337

AC:

1170

AN:

3464

show subpopulations

Oceania

AF:

0.205

AC:

AN:

146

Hom.:

North-East Asia

AF:

0.283

AC:

199

AN:

702

Hom.:

South-East Asia

AF:

0.259

AC:

179

AN:

690

Hom.:

South Asia

AF:

0.428

AC:

620

AN:

1448

Hom.:

149

Africa

AF:

0.260

AC:

AN:

204

Hom.:

America

AF:

0.420

AC:

AN:

Hom.:

West Eurasia

AF:

0.304

AC:

AN:

224

Hom.:

Korea4K (4,157 Koreans)

AF:

0.275

AC:

1972

AN:

7174

Qatari Genome

AF:

0.295

AC:

AN:

176

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.277

AC:

33747

AN:

121754

Hom.:

4753

Turkish Variome

AF:

0.276

AC:

426

AN:

1546

Hom.:

UK10K

AF:

0.318

AC:

2406

AN:

7562

show subpopulations

TwinsUK

AF:

0.315

AC:

1126

AN:

3574

ALSPAC

AF:

0.320

AC:

1232

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.292

AC:

2618

AN:

8960

Hom.:

372

Case/control cohorts

Cohort

Cases

Controls

SCHEMA

(Schizophrenia)

39170 / 118816AF: 0.329669

62020 / 179310AF: 0.345881

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Congenital Muscular Dystrophy, alpha-dystroglycan related (1)

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 (1)

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

3.4

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0014

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-1.7

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.20

REVEL

Benign

0.14

Sift

Benign

0.88

Sift4G

Benign

0.66

PromoterAI

0.12

Neutral

(source)

Varity_R

0.046

popEVE

Benign

-3.0

(source)

VESM-3B

Benign

-2.4

(source)

FuncVEP CTI

Benign

0.0019

(source)

AlphaGenome AVI

Benign

5.2

(source)

GPN-Star LLR

-1.1

(source)

GPN-Star score

1.1

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.0

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over