chr7-16308536-G-A

Variant names:

• chr7-16308536-G-A
• rs369193825
• NM_001101426.4:c.776C>T

Variant summary

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

The NM_001101426.4(CRPPA):​c.776C>T​(p.Pro259Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,597,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P259P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.10
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	NM_001101426.4	MANE Select	c.776C>T	p.Pro259Leu	missense	Exon 4 of 10	NP_001094896.1
	CRPPA	NM_001101417.4		c.626C>T	p.Pro209Leu	missense	Exon 3 of 9	NP_001094887.1
	CRPPA	NM_001368197.1		c.685-7070C>T		intron	N/A	NP_001355126.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.776C>T	p.Pro259Leu	missense	Exon 4 of 10	ENSP00000385478.2
	CRPPA	ENST00000399310.3	TSL:1	c.626C>T	p.Pro209Leu	missense	Exon 3 of 9	ENSP00000382249.3
	CRPPA	ENST00000856526.1		c.776C>T	p.Pro259Leu	missense	Exon 4 of 8	ENSP00000526585.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000330 AC: 8 AN: 242534 AF XY: 0.0000229

Gnomad AFR exome AF: 0.000531

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: 0.0000104 AC: 15 AN: 1445036 Hom.: 0 Cov.: 28 AF XY: 0.00000974 AC XY: 7 AN XY: 719038

African (AFR) AF: 0.000423 AC: 14 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 44246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 84626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098758

Other (OTH) AF: 0.0000167 AC: 1 AN: 59830

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152142 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74316

African (AFR) AF: 0.000290 AC: 12 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.000256 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000414 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.1
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.58
Sift	Benign	0.33	T
Sift4G	Uncertain	0.037	D
Polyphen		0.13	B
Vest4		0.53
MVP		0.70
MPC		0.28
ClinPred		0.81	D
GERP RS		5.3
Varity_R		0.65
gMVP		0.71
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs369193825; hg19: chr7-16348161; COSMIC: COSV67908106;