rs61744487

Positions:

Variant summary

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

The NM_001101426.4(CRPPA):c.346C>T(p.Arg116Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00099 in 1,613,878 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 5 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 11 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.63

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012536794).

BP6

Variant 7-16406249-G-A is Benign according to our data. Variant chr7-16406249-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 359592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00521 (793/152252) while in subpopulation AFR AF= 0.018 (748/41554). AF 95% confidence interval is 0.0169. There are 5 homozygotes in gnomad4. There are 391 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CRPPA	NM_001101426.4 linkuse as main transcript	c.346C>T	p.Arg116Cys	missense_variant	2/10	ENST00000407010.7	NP_001094896.1
CRPPA	NM_001368197.1 linkuse as main transcript	c.346C>T	p.Arg116Cys	missense_variant	2/9		NP_001355126.1
CRPPA	NM_001101417.4 linkuse as main transcript	c.346C>T	p.Arg116Cys	missense_variant	2/9		NP_001094887.1
CRPPA	NR_160656.1 linkuse as main transcript	n.562C>T		non_coding_transcript_exon_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7 linkuse as main transcript	c.346C>T	p.Arg116Cys	missense_variant	2/10	5	NM_001101426.4	ENSP00000385478	P1	A4D126-1

Frequencies

GnomAD3 genomes

AF:

0.00521

AC:

793

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00128

AC:

320

AN:

249070

Hom.:

AF XY:

0.000962

AC XY:

130

AN XY:

135114

show subpopulations

Gnomad AFR exome

AF:

0.0170

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000550

AC:

804

AN:

1461626

Hom.:

Cov.:

AF XY:

0.000469

AC XY:

341

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.0177

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00521

AC:

793

AN:

152252

Hom.:

Cov.:

AF XY:

0.00525

AC XY:

391

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0180

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00213

Hom.:

Bravo

AF:

0.00602

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0189

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00159

AC:

192

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CRPPA: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2018	This variant is associated with the following publications: (PMID: 28688748) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 09, 2018

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Congenital Muscular Dystrophy, alpha-dystroglycan related

Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.

Eigen

Benign

0.017

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.60

MVP

0.69

MPC

0.38

ClinPred

0.035

GERP RS

0.060

Varity_R

0.88

gMVP

0.64

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

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