7-16376161-AC-GT

Variant names:

• chr7-16376161-AC-GT
• NM_001101426.4:c.614_615delGTinsAC
• CRPPA p.Arg205His

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1_Moderate PM5

The NM_001101426.4(CRPPA):​c.614_615delGTinsAC​(p.Arg205His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R205L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.11
• 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 4 ACMG points.

• PS1: Transcript NM_001101426.4 (CRPPA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-16376163-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 424305.Status of the report is criteria_provided_single_submitter, 1 stars.

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.614_615delGTinsAC	p.Arg205His	missense	N/A	NP_001094896.1	A4D126-1
	CRPPA	NM_001368197.1		c.614_615delGTinsAC	p.Arg205His	missense	N/A	NP_001355126.1
	CRPPA	NM_001101417.4		c.534+29899_534+29900delGTinsAC		intron	N/A	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.614_615delGTinsAC	p.Arg205His	missense	N/A	ENSP00000385478.2	A4D126-1
	CRPPA	ENST00000399310.3	TSL:1	c.534+29899_534+29900delGTinsAC		intron	N/A	ENSP00000382249.3	A4D126-2
	CRPPA	ENST00000856526.1		c.614_615delGTinsAC	p.Arg205His	missense	N/A	ENSP00000526585.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

Splicing

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

hg19: chr7-16415786;