chr7-16421269-C-CA

Variant names:

• chr7-16421269-C-CA
• rs886041302
• NM_001101426.4:c.53dupT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001101426.4(CRPPA):​c.53dupT​(p.Ser19GlufsTer97) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,296,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L18L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CRPPA NM_001101426.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.581
• Publications: 4 publications found

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

ENSG00000272537 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 45 pathogenic variants in the truncated region.
• PP5: Variant 7-16421269-C-CA is Pathogenic according to our data. Variant chr7-16421269-C-CA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 279985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	NM_001101426.4	MANE Select	c.53dupT	p.Ser19GlufsTer97	frameshift	Exon 1 of 10	NP_001094896.1
	CRPPA	NM_001368197.1		c.53dupT	p.Ser19GlufsTer97	frameshift	Exon 1 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.53dupT	p.Ser19GlufsTer97	frameshift	Exon 1 of 9	NP_001094887.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.53dupT	p.Ser19GlufsTer97	frameshift	Exon 1 of 10	ENSP00000385478.2
	CRPPA	ENST00000399310.3	TSL:1	c.53dupT	p.Ser19GlufsTer97	frameshift	Exon 1 of 9	ENSP00000382249.3
	CRPPA	ENST00000675257.1		c.-46-14933dupT		intron	N/A	ENSP00000501664.1

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151810 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 13638 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 130 AN: 1144948 Hom.: 0 Cov.: 32 AF XY: 0.0000912 AC XY: 50 AN XY: 547966

African (AFR) AF: 0.00 AC: 0 AN: 23320

American (AMR) AF: 0.00 AC: 0 AN: 9626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15600

East Asian (EAS) AF: 0.00 AC: 0 AN: 26766

South Asian (SAS) AF: 0.00 AC: 0 AN: 33952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3274

European-Non Finnish (NFE) AF: 0.000129 AC: 122 AN: 948158

Other (OTH) AF: 0.000175 AC: 8 AN: 45836

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151810 Hom.: 0 Cov.: 33 AF XY: 0.0000944 AC XY: 7 AN XY: 74160

African (AFR) AF: 0.0000726 AC: 3 AN: 41342

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67914

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000907

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Aug 26, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 25, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 17, 2024

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the CRPPA gene demonstrated a single base pair deletion in exon 1, c.53dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 96 amino acids downstream of the change, p.Ser19Glufs*97. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CRPPA protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.01% in the global population (dbSNP rs886041302). This pathogenic sequence change has previously been described in the compound heterozygous state with other pathogenic variants in individuals with CRPPA-related disorders (PMID: 22522421, 23288328). These collective evidences indicate that this sequence change is pathogenic, however functional studies have not been performed to prove this conclusively.

Oct 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23288328, 22522421, 31980526)

Sep 21, 2021

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org).

not specified Pathogenic:1

Apr 08, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.53dupT (p.S19Efs*97) alteration, located in exon 1 (coding exon 1) of the ISPD gene, consists of a duplication of T at position 53, causing a translational frameshift with a predicted alternate stop codon after 97 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the available evidence, this alteration is classified as pathogenic.

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

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser19Glufs*97) in the ISPD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ISPD are known to be pathogenic (PMID: 23288328). This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Walker-Warburg syndrome or autosomal recessive limb girdle muscular dystrophy with intellectual disability (PMID: 2328832, 22522421). ClinVar contains an entry for this variant (Variation ID: 279985). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.58
Mutation Taster		=7/193	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886041302; hg19: chr7-16460894;