7-16308637-AAACAACAAC-AAACAAC

Variant names:

• chr7-16308637-AAAC-A
• rs142647500
• NM_001101426.4:c.685-13_685-11delGTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001101426.4(CRPPA):​c.685-13_685-11delGTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,403,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: CRPPA NM_001101426.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.808
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 7-16308637-AAAC-A is Benign according to our data. Variant chr7-16308637-AAAC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1680776.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRPPA	NM_001101426.4	c.685-13_685-11delGTT		intron_variant	Intron 3 of 9	ENST00000407010.7	NP_001094896.1
CRPPA	NM_001368197.1	c.685-7174_685-7172delGTT		intron_variant	Intron 3 of 8		NP_001355126.1
CRPPA	NM_001101417.4	c.535-13_535-11delGTT		intron_variant	Intron 2 of 8		NP_001094887.1
CRPPA	NR_160656.1	n.901-30414_901-30412delGTT		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7	c.685-13_685-11delGTT		intron_variant	Intron 3 of 9	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000283 AC: 62 AN: 219382 AF XY: 0.000330

Gnomad AFR exome AF: 0.000147

Gnomad AMR exome AF: 0.000132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000192

Gnomad FIN exome AF: 0.000200

Gnomad NFE exome AF: 0.000377

Gnomad OTH exome AF: 0.000367

GnomAD4 exome AF: 0.000336 AC: 420 AN: 1251576 Hom.: 0 AF XY: 0.000353 AC XY: 223 AN XY: 631862

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000422 AC: 12 AN: 28452

American (AMR) AF: 0.0000953 AC: 4 AN: 41980

Ashkenazi Jewish (ASJ) AF: 0.0000407 AC: 1 AN: 24568

East Asian (EAS) AF: 0.00209 AC: 79 AN: 37836

South Asian (SAS) AF: 0.000379 AC: 30 AN: 79172

European-Finnish (FIN) AF: 0.0000950 AC: 5 AN: 52610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5414

European-Non Finnish (NFE) AF: 0.000297 AC: 276 AN: 928516

Other (OTH) AF: 0.000245 AC: 13 AN: 53028

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74326

African (AFR) AF: 0.000193 AC: 8 AN: 41436

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

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

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

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

Alfa AF: 0.000449 Hom.: 12

Bravo AF: 0.000121

ClinVar

Significance: Likely benign

Submissions summary: Benign: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 Benign:1

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs142647500; hg19: chr7-16348262;