rs1292380177

Variant names:

• chr7-16421102-C-A
• rs1292380177
• NM_001101426.4:c.221G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-16421102-C-A
• chr7-16421102-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001101426.4(CRPPA):​c.221G>T​(p.Arg74Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000871 in 1,148,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R74T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.27
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757

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.221G>T	p.Arg74Met	missense	Exon 1 of 10	NP_001094896.1
	CRPPA	NM_001368197.1		c.221G>T	p.Arg74Met	missense	Exon 1 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.221G>T	p.Arg74Met	missense	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.221G>T	p.Arg74Met	missense	Exon 1 of 10	ENSP00000385478.2
	CRPPA	ENST00000399310.3	TSL:1	c.221G>T	p.Arg74Met	missense	Exon 1 of 9	ENSP00000382249.3
	CRPPA	ENST00000675257.1		c.-46-14765G>T		intron	N/A	ENSP00000501664.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.71e-7 AC: 1 AN: 1148760 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 550870

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

African (AFR) AF: 0.00 AC: 0 AN: 23476

American (AMR) AF: 0.00 AC: 0 AN: 9190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15362

East Asian (EAS) AF: 0.00 AC: 0 AN: 26898

South Asian (SAS) AF: 0.00 AC: 0 AN: 34430

European-Finnish (FIN) AF: 0.0000256 AC: 1 AN: 39026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 949650

Other (OTH) AF: 0.00 AC: 0 AN: 46024

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	30
DANN	Benign	0.97
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.73
Sift	Benign	0.046	D
Sift4G	Uncertain	0.033	D
Polyphen		0.99	D
Vest4		0.60
MutPred		0.64		Loss of catalytic residue at R74 (P = 0.0148)
MVP		0.63
MPC		0.25
ClinPred		0.98	D
GERP RS		4.5
PromoterAI		-0.13	Neutral
Varity_R		0.79
gMVP		0.79
Mutation Taster		=30/70	disease causing

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: rs1292380177; hg19: chr7-16460727;