7-16258455-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001101426.4(CRPPA):c.1054C>A(p.Gln352Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,603,468 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 9 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.780

Publications

3 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 links:

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

CRPPA-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002675265).

BP6

Variant 7-16258455-G-T is Benign according to our data. Variant chr7-16258455-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198766.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CRPPA	NM_001101426.4	MANE Select	c.1054C>A	p.Gln352Lys	missense	Exon 8 of 10	NP_001094896.1
CRPPA	NM_001368197.1		c.949C>A	p.Gln317Lys	missense	Exon 7 of 9	NP_001355126.1
CRPPA	NM_001101417.4		c.904C>A	p.Gln302Lys	missense	Exon 7 of 9	NP_001094887.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.1054C>A	p.Gln352Lys	missense	Exon 8 of 10	ENSP00000385478.2
CRPPA	ENST00000399310.3	TSL:1	c.904C>A	p.Gln302Lys	missense	Exon 7 of 9	ENSP00000382249.3
CRPPA-AS1	ENST00000438573.5	TSL:1	n.222-3444G>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

213

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000850

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00232

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00137

AC:

327

AN:

238306

AF XY:

0.00142

show subpopulations

Gnomad AFR exome

AF:

0.000137

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.000723

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000427

Gnomad NFE exome

AF:

0.00268

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.00243

AC:

3524

AN:

1451372

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

1722

AN XY:

721608

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000242

AC:

AN:

33106

American (AMR)

AF:

0.000115

AC:

AN:

43622

Ashkenazi Jewish (ASJ)

AF:

0.000620

AC:

AN:

25820

East Asian (EAS)

AF:

0.00

AC:

AN:

39318

South Asian (SAS)

AF:

0.000249

AC:

AN:

84480

European-Finnish (FIN)

AF:

0.000776

AC:

AN:

52864

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00302

AC:

3344

AN:

1106488

Other (OTH)

AF:

0.00145

AC:

AN:

59942

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.382

Heterozygous variant carriers

135

271

406

542

677

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<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:

0.00140

AC:

213

AN:

152096

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41524

American (AMR)

AF:

0.000197

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000850

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00233

AC:

158

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000620

Hom.:

Bravo

AF:

0.00139

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000554

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00196

AC:

236

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CRPPA: BP4

May 18, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 17, 2020

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 23, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital Muscular Dystrophy, alpha-dystroglycan related

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, 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.

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

Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0064

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.61

M_CAP

Benign

0.020

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.8

PhyloP100

0.78

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.070

REVEL

Benign

0.060

Sift

Benign

0.59

Sift4G

Benign

0.90

Polyphen

0.085

Vest4

0.18

MVP

0.49

MPC

0.070

ClinPred

0.0012

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.44

Mutation Taster

=90/10

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over