7-16421162-C-G

Variant names:

• chr7-16421162-C-G
• rs587777797
• NM_001101426.4:c.161G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001101426.4(CRPPA):​c.161G>C​(p.Gly54Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G54V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.17
• Publications: 2 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79
• PP5: Variant 7-16421162-C-G is Pathogenic according to our data. Variant chr7-16421162-C-G is described in CliVar as Pathogenic. Clinvar id is 156454.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-16421162-C-G is described in CliVar as Pathogenic. Clinvar id is 156454.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-16421162-C-G is described in CliVar as Pathogenic. Clinvar id is 156454.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-16421162-C-G is described in CliVar as Pathogenic. Clinvar id is 156454.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-16421162-C-G is described in CliVar as Pathogenic. Clinvar id is 156454.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-16421162-C-G is described in CliVar as Pathogenic. Clinvar id is 156454.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-16421162-C-G is described in CliVar as Pathogenic. Clinvar id is 156454.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-16421162-C-G is described in CliVar as Pathogenic. Clinvar id is 156454.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-16421162-C-G is described in CliVar as Pathogenic. Clinvar id is 156454.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRPPA	NM_001101426.4	c.161G>C	p.Gly54Ala	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.161G>C	p.Gly54Ala	missense_variant	Exon 1 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2U Pathogenic:1

Mar 05, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.12	N;N
PhyloP100		5.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.63
Sift	Benign	0.61	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.96	D;.
Vest4		0.61
MutPred		0.59		Loss of catalytic residue at A53 (P = 0.0534);Loss of catalytic residue at A53 (P = 0.0534);
MVP		0.65
MPC		0.097
ClinPred		0.80	D
GERP RS		4.3
PromoterAI		-0.018	Neutral
Varity_R		0.46
gMVP		0.81
Mutation Taster		=5/95	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: rs587777797; hg19: chr7-16460787;