rs199691459

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001101426.4(CRPPA):c.320G>T(p.Ser107Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000239 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.175

Publications

3 publications found

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 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

CRPPA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.1382465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CRPPA	NM_001101426.4 link	c.320G>T	p.Ser107Ile	missense_variant	Exon 2 of 10	ENST00000407010.7	NP_001094896.1
CRPPA	NM_001368197.1 link	c.320G>T	p.Ser107Ile	missense_variant	Exon 2 of 9		NP_001355126.1
CRPPA	NM_001101417.4 link	c.320G>T	p.Ser107Ile	missense_variant	Exon 2 of 9		NP_001094887.1
CRPPA	NR_160656.1 link	n.536G>T		non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7 link	c.320G>T	p.Ser107Ile	missense_variant	Exon 2 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000112

AC:

AN:

249022

AF XY:

0.0000740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000204

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000253

AC:

370

AN:

1461592

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

177

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000303

AC:

337

AN:

1111800

Other (OTH)

AF:

0.000215

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000222

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.0000828

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 19, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.320G>T (p.S107I) alteration is located in exon 2 (coding exon 2) of the ISPD gene. This alteration results from a G to T substitution at nucleotide position 320, causing the serine (S) at amino acid position 107 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Jul 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 107 of the ISPD protein (p.Ser107Ile). This variant is present in population databases (rs199691459, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ISPD-related conditions. ClinVar contains an entry for this variant (Variation ID: 285066). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Congenital Muscular Dystrophy, alpha-dystroglycan related

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.57

D;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.80

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

2.0

M;M

PhyloP100

0.17

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.4

D;D

REVEL

Benign

0.14

Sift

Benign

0.069

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.47

P;.

Vest4

0.36

MVP

0.42

MPC

0.15

ClinPred

0.095

GERP RS

1.6

Varity_R

0.32

gMVP

0.40

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over