rs192925278

Variant names:

• chr7-16421291-G-A
• rs192925278
• NM_001101426.4:c.32C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-16421291-G-A
• chr7-16421291-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001101426.4(CRPPA):​c.32C>T​(p.Pro11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000179 in 1,118,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.869
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28733158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRPPA	NM_001101426.4	c.32C>T	p.Pro11Leu	missense_variant	Exon 1 of 10	ENST00000407010.7	NP_001094896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7	c.32C>T	p.Pro11Leu	missense_variant	Exon 1 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000179 AC: 2 AN: 1118756 Hom.: 0 Cov.: 32 AF XY: 0.00000188 AC XY: 1 AN XY: 532460

African (AFR) AF: 0.00 AC: 0 AN: 22976

American (AMR) AF: 0.00 AC: 0 AN: 8490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14830

East Asian (EAS) AF: 0.00 AC: 0 AN: 26364

South Asian (SAS) AF: 0.00 AC: 0 AN: 27866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3004

European-Non Finnish (NFE) AF: 0.00000214 AC: 2 AN: 935178

Other (OTH) AF: 0.00 AC: 0 AN: 44730

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jul 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 934867). This variant has not been reported in the literature in individuals affected with ISPD-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 11 of the ISPD protein (p.Pro11Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0091	T;.
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.66	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.0	N;N
PhyloP100		0.87
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.037	D;D
Polyphen		0.99	D;.
Vest4		0.23
MutPred		0.20		Loss of glycosylation at P11 (P = 0.0472);Loss of glycosylation at P11 (P = 0.0472);
MVP		0.62
MPC		0.17
ClinPred		0.77	D
GERP RS		3.0
PromoterAI		-0.19	Neutral
Varity_R		0.23
gMVP		0.62
Mutation Taster		=91/9	polymorphism

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: rs192925278; hg19: chr7-16460916;