rs61746966

Positions:

• chr7-16308586-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001101426.4(CRPPA):​c.726A>G​(p.Gln242=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,611,086 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (168 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (137 hom.)
• Consequence: CRPPA NM_001101426.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.02

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-16308586-T-C is Benign according to our data. Variant chr7-16308586-T-C is described in ClinVar as [Benign]. Clinvar id is 129289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-16308586-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.091 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4	c.726A>G	p.Gln242=	synonymous_variant	4/10	ENST00000407010.7
CRPPA	NM_001101417.4	c.576A>G	p.Gln192=	synonymous_variant	3/9
CRPPA	NM_001368197.1	c.685-7120A>G		intron_variant
CRPPA	NR_160656.1	n.901-30360A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7	c.726A>G	p.Gln242=	synonymous_variant	4/10	5	NM_001101426.4	P1

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4107 AN: 152124 Hom.: 165 Cov.: 33

Gnomad AFR AF: 0.0931

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00704 AC: 1729 AN: 245698 Hom.: 68 AF XY: 0.00529 AC XY: 704 AN XY: 133030

Gnomad AFR exome AF: 0.0968

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00492

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000270

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.00484

GnomAD4 exome AF: 0.00274 AC: 3996 AN: 1458844 Hom.: 137 Cov.: 29 AF XY: 0.00231 AC XY: 1679 AN XY: 725450

Gnomad4 AFR exome AF: 0.0945

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.00437

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000199

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.00564

GnomAD4 genome AF: 0.0271 AC: 4133 AN: 152242 Hom.: 168 Cov.: 33 AF XY: 0.0268 AC XY: 1993 AN XY: 74432

Gnomad4 AFR AF: 0.0935

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0131 Hom.: 52

Bravo AF: 0.0311

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Invitae

Jan 30, 2024

- -

Congenital Muscular Dystrophy, alpha-dystroglycan related Benign:1

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 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
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.18
DANN	Benign	0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs61746966; hg19: chr7-16348211; COSMIC: COSV67906051;