rs939213590

Variant names:

• chr7-16421097-G-C
• rs939213590
• NM_001101426.4:c.226C>G
• CRPPA p.Leu76Val

Variant summary

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

The NM_001101426.4(CRPPA):​c.226C>G​(p.Leu76Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,298,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.65
• 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• 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 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.226C>G	p.Leu76Val	missense	Exon 1 of 10	NP_001094896.1	A4D126-1
	CRPPA	NM_001368197.1		c.226C>G	p.Leu76Val	missense	Exon 1 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.226C>G	p.Leu76Val	missense	Exon 1 of 9	NP_001094887.1	A0A140VJM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.226C>G	p.Leu76Val	missense	Exon 1 of 10	ENSP00000385478.2	A4D126-1
	CRPPA	ENST00000399310.3	TSL:1	c.226C>G	p.Leu76Val	missense	Exon 1 of 9	ENSP00000382249.3	A4D126-2
	CRPPA	ENST00000856526.1		c.226C>G	p.Leu76Val	missense	Exon 1 of 8	ENSP00000526585.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152088 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

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

GnomAD4 exome AF: 0.00000523 AC: 6 AN: 1146588 Hom.: 0 Cov.: 31 AF XY: 0.00000546 AC XY: 3 AN XY: 549628

African (AFR) AF: 0.000256 AC: 6 AN: 23450

American (AMR) AF: 0.00 AC: 0 AN: 9134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15304

East Asian (EAS) AF: 0.00 AC: 0 AN: 26888

South Asian (SAS) AF: 0.00 AC: 0 AN: 33888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 948520

Other (OTH) AF: 0.00 AC: 0 AN: 45892

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152088 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74300

African (AFR) AF: 0.000217 AC: 9 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000132

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)
-	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	Benign	0.16
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.2	L
PhyloP100		6.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.65
Sift	Benign	0.23	T
Sift4G	Benign	0.099	T
PromoterAI		-0.033	Neutral
Varity_R		0.73
gMVP		0.64
Mutation Taster		=16/84	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs939213590;

hg19: chr7-16460722;