rs750477422

Variant names:

• chr7-16278215-G-C
• rs750477422
• NM_001101426.4:c.847C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001101426.4(CRPPA):​c.847C>G​(p.Gln283Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,389,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2664151).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRPPA	NM_001101426.4	c.847C>G	p.Gln283Glu	missense_variant	Exon 6 of 10	ENST00000407010.7	NP_001094896.1
CRPPA	NM_001368197.1	c.742C>G	p.Gln248Glu	missense_variant	Exon 5 of 9		NP_001355126.1
CRPPA	NM_001101417.4	c.697C>G	p.Gln233Glu	missense_variant	Exon 5 of 9		NP_001094887.1
CRPPA	NR_160656.1	n.912C>G		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7	c.847C>G	p.Gln283Glu	missense_variant	Exon 6 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1389950 Hom.: 0 Cov.: 23 AF XY: 0.00000144 AC XY: 1 AN XY: 692596

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000831 AC: 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

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0028	T;.
Eigen	Benign	0.027
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.92	P;.
Vest4		0.28
MutPred		0.43		Gain of loop (P = 0.069);.;
MVP		0.77
MPC		0.062
ClinPred		0.41	T
GERP RS		4.3
Varity_R		0.30
gMVP		0.53

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

Other links and lift over

dbSNP: rs750477422; hg19: chr7-16317840;