rs199691459

Variant names:

• chr7-16406275-C-A
• rs199691459
• NM_001101426.4:c.320G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-16406275-C-A
• chr7-16406275-C-G

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.175
• Publications: 3 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1382465).

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.320G>T	p.Ser107Ile	missense	Exon 2 of 10	NP_001094896.1	A4D126-1
	CRPPA	NM_001368197.1		c.320G>T	p.Ser107Ile	missense	Exon 2 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.320G>T	p.Ser107Ile	missense	Exon 2 of 9	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.320G>T	p.Ser107Ile	missense	Exon 2 of 10	ENSP00000385478.2	A4D126-1
	CRPPA	ENST00000399310.3	TSL:1	c.320G>T	p.Ser107Ile	missense	Exon 2 of 9	ENSP00000382249.3	A4D126-2
	CRPPA	ENST00000856526.1		c.320G>T	p.Ser107Ile	missense	Exon 2 of 8	ENSP00000526585.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152162 Hom.: 0 Cov.: 33

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: 28 AN: 249022 AF XY: 0.0000740

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.: 0 Cov.: 32 AF XY: 0.000243 AC XY: 177 AN XY: 727082

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000303 AC: 337 AN: 1111800

Other (OTH) AF: 0.000215 AC: 13 AN: 60364

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74334

African (AFR) AF: 0.0000483 AC: 2 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000222 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.0000828 AC: 10

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Congenital Muscular Dystrophy, alpha-dystroglycan related (1)
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.17
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.14
Sift	Benign	0.069	T
Sift4G	Benign	0.19	T
Polyphen		0.47	P
Vest4		0.36
MVP		0.42
MPC		0.15
ClinPred		0.095	T
GERP RS		1.6
Varity_R		0.32
gMVP		0.40
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs199691459; hg19: chr7-16445900;