7-16216099-A-C

Position:

chr7-16216099-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001101426.4(CRPPA):c.1218T>G(p.Ile406Met) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,602,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 4.62

Variant links:

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 links:

CRPPA-AS1 (HGNC:48962): (CRPPA antisense RNA 1)

CRPPA-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026915282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRPPA	NM_001101426.4 linkuse as main transcript	c.1218T>G	p.Ile406Met	missense_variant	9/10	ENST00000407010.7	NP_001094896.1
CRPPA-AS1	NR_038947.1 linkuse as main transcript	n.118+5496A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7 linkuse as main transcript	c.1218T>G	p.Ile406Met	missense_variant	9/10	5	NM_001101426.4	ENSP00000385478	P1	A4D126-1
CRPPA-AS1	ENST00000438573.5 linkuse as main transcript	n.116+5496A>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.000558

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000478

GnomAD3 exomes

AF:

0.000148

AC:

AN:

243710

Hom.:

AF XY:

0.000129

AC XY:

AN XY:

131926

show subpopulations

Gnomad AFR exome

AF:

0.00202

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000566

AC:

AN:

1449940

Hom.:

Cov.:

AF XY:

0.0000430

AC XY:

AN XY:

721320

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.0000917

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.000134

GnomAD4 genome

AF:

0.000571

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00204

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000687

Hom.:

Bravo

AF:

0.000740

ESP6500AA

AF:

0.00223

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000116

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 03, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2016	The I406M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I406M variant is observed in 14/9632 (0.15%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server)]. This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 30, 2020	- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 406 of the ISPD protein (p.Ile406Met). This variant is present in population databases (rs202011820, gnomAD 0.2%). This missense change has been observed in individual(s) with muscular dystrophy (PMID: 29382405). ClinVar contains an entry for this variant (Variation ID: 429621). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.027

T;T

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.97

D;.

Vest4

0.37

MVP

0.66

MPC

0.32

ClinPred

0.064

GERP RS

5.1

Varity_R

0.53

gMVP

0.60

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over