rs61746966

Variant names:

• chr7-16308586-T-C
• rs61746966
• NM_001101426.4:c.726A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001101426.4(CRPPA):​c.726A>G​(p.Gln242Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,611,086 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (168 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (137 hom.)
• Consequence: CRPPA NM_001101426.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.02
• Publications: 1 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-16308586-T-C is Benign according to our data. Variant chr7-16308586-T-C is described in ClinVar as Benign. ClinVar VariationId is 129289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.091 is higher than 0.05.

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.726A>G	p.Gln242Gln	synonymous	Exon 4 of 10	NP_001094896.1
	CRPPA	NM_001101417.4		c.576A>G	p.Gln192Gln	synonymous	Exon 3 of 9	NP_001094887.1
	CRPPA	NM_001368197.1		c.685-7120A>G		intron	N/A	NP_001355126.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.726A>G	p.Gln242Gln	synonymous	Exon 4 of 10	ENSP00000385478.2
	CRPPA	ENST00000399310.3	TSL:1	c.576A>G	p.Gln192Gln	synonymous	Exon 3 of 9	ENSP00000382249.3
	CRPPA	ENST00000676325.1		c.423A>G	p.Gln141Gln	synonymous	Exon 5 of 11	ENSP00000502074.1

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4107 AN: 152124 Hom.: 165 Cov.: 33

Gnomad AFR AF: 0.0931

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00704 AC: 1729 AN: 245698 AF XY: 0.00529

Gnomad AFR exome AF: 0.0968

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00492

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.00484

GnomAD4 exome AF: 0.00274 AC: 3996 AN: 1458844 Hom.: 137 Cov.: 29 AF XY: 0.00231 AC XY: 1679 AN XY: 725450

African (AFR) AF: 0.0945 AC: 3152 AN: 33356

American (AMR) AF: 0.00503 AC: 224 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.00437 AC: 114 AN: 26058

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39664

South Asian (SAS) AF: 0.000199 AC: 17 AN: 85430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5766

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1110458

Other (OTH) AF: 0.00564 AC: 340 AN: 60282

GnomAD4 genome AF: 0.0271 AC: 4133 AN: 152242 Hom.: 168 Cov.: 33 AF XY: 0.0268 AC XY: 1993 AN XY: 74432

African (AFR) AF: 0.0935 AC: 3881 AN: 41530

American (AMR) AF: 0.0110 AC: 168 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68022

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.0132 Hom.: 63

Bravo AF: 0.0311

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Congenital Muscular Dystrophy, alpha-dystroglycan related (1)
-	-	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
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.18
DANN	Benign	0.27
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs61746966; hg19: chr7-16348211; COSMIC: COSV67906051;