7-16421266-ACT-TCG

Variant names:

• chr7-16421266-ACT-TCG
• NM_001101426.4:c.55_57delAGTinsCGA
• CRPPA p.Ser19Arg

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001101426.4(CRPPA):c.55_57delAGTinsCGA (p.Ser19Arg) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S19R: Benign (ClinVar VariationId 129288, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.106
• 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, STRONG Submitted by: PanelApp Australia, 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:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001101426.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CRPPA NM_001101426.4	MANE Select	c.55_57delAGTinsCGA p.Ser19Arg	missense	N/A	Prot: NP_001094896.1 UniProt:
	CRPPA NM_001368197.1		c.55_57delAGTinsCGA p.Ser19Arg	missense	N/A	Prot: NP_001355126.1
	CRPPA NM_001101417.4		c.55_57delAGTinsCGA p.Ser19Arg	missense	N/A	Prot: NP_001094887.1 UniProt:

CRPPA NM_001101426.4

MANE Select

HGVSc / HGVSpc.55_57delAGTinsCGAp.Ser19Arg

Exon rankN/A

missense

Prot: NP_001094896.1UniProt: A4D126-1

CRPPA NM_001368197.1

HGVSc / HGVSpc.55_57delAGTinsCGAp.Ser19Arg

Exon rankN/A

missense

Prot: NP_001355126.1

CRPPA NM_001101417.4

HGVSc / HGVSpc.55_57delAGTinsCGAp.Ser19Arg

Exon rankN/A

missense

Prot: NP_001094887.1UniProt: A0A140VJM1A4D126-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CRPPA ENST00000407010.7	TSL:5MANE Select	c.55_57delAGTinsCGA p.Ser19Arg	missense	N/A	Prot: ENSP00000385478.2 UniProt:
	CRPPA ENST00000399310.3	TSL:1	c.55_57delAGTinsCGA p.Ser19Arg	missense	N/A	Prot: ENSP00000382249.3 UniProt:
	CRPPA ENST00000856526.1		c.55_57delAGTinsCGA p.Ser19Arg	missense	N/A	Prot: ENSP00000526585.1 UniProt:

CRPPA ENST00000407010.7

TSL:5MANE Select

HGVSc / HGVSpc.55_57delAGTinsCGAp.Ser19Arg

Exon rankN/A

missense

Prot: ENSP00000385478.2UniProt: A4D126-1

CRPPA ENST00000399310.3

TSL:1

HGVSc / HGVSpc.55_57delAGTinsCGAp.Ser19Arg

Exon rankN/A

missense

Prot: ENSP00000382249.3UniProt: A4D126-2

CRPPA ENST00000856526.1

HGVSc / HGVSpc.55_57delAGTinsCGAp.Ser19Arg

Exon rankN/A

missense

Prot: ENSP00000526585.1UniProt: A0ACI8QS87

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.11

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr7-16460891;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar