chr7-16406188-G-A

Variant names:

• chr7-16406188-G-A
• rs61734789
• NM_001101426.4:c.407C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001101426.4(CRPPA):​c.407C>T​(p.Ala136Val) variant causes a missense change. The variant allele was found at a frequency of 0.0365 in 1,613,930 control chromosomes in the GnomAD database, including 1,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A136A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (59 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1274 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.21
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010987341).
• BP6: Variant 7-16406188-G-A is Benign according to our data. Variant chr7-16406188-G-A is described in ClinVar as Benign. ClinVar VariationId is 129287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.024 (3654/152308) while in subpopulation NFE AF = 0.0381 (2594/68026). AF 95% confidence interval is 0.0369. There are 59 homozygotes in GnomAd4. There are 1700 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 AR gene

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.407C>T	p.Ala136Val	missense	Exon 2 of 10	NP_001094896.1	A4D126-1
	CRPPA	NM_001368197.1		c.407C>T	p.Ala136Val	missense	Exon 2 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.407C>T	p.Ala136Val	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.407C>T	p.Ala136Val	missense	Exon 2 of 10	ENSP00000385478.2	A4D126-1
	CRPPA	ENST00000399310.3	TSL:1	c.407C>T	p.Ala136Val	missense	Exon 2 of 9	ENSP00000382249.3	A4D126-2
	CRPPA	ENST00000856526.1		c.407C>T	p.Ala136Val	missense	Exon 2 of 8	ENSP00000526585.1

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3657 AN: 152190 Hom.: 59 Cov.: 33

Gnomad AFR AF: 0.00849

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0382

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0232 AC: 5776 AN: 249146 AF XY: 0.0239

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.00864

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0378 AC: 55266 AN: 1461622 Hom.: 1274 Cov.: 33 AF XY: 0.0367 AC XY: 26681 AN XY: 727106

African (AFR) AF: 0.00612 AC: 205 AN: 33480

American (AMR) AF: 0.00899 AC: 402 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00421 AC: 110 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0128 AC: 1106 AN: 86258

European-Finnish (FIN) AF: 0.0246 AC: 1312 AN: 53400

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0451 AC: 50120 AN: 1111800

Other (OTH) AF: 0.0330 AC: 1991 AN: 60372

GnomAD4 genome AF: 0.0240 AC: 3654 AN: 152308 Hom.: 59 Cov.: 33 AF XY: 0.0228 AC XY: 1700 AN XY: 74468

African (AFR) AF: 0.00847 AC: 352 AN: 41576

American (AMR) AF: 0.0190 AC: 291 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4828

European-Finnish (FIN) AF: 0.0236 AC: 250 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0381 AC: 2594 AN: 68026

Other (OTH) AF: 0.0265 AC: 56 AN: 2110

Alfa AF: 0.0331 Hom.: 347

Bravo AF: 0.0231

ESP6500AA AF: 0.00937 AC: 36

ESP6500EA AF: 0.0352 AC: 290

ExAC AF: 0.0241 AC: 2909

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0329

EpiControl AF: 0.0350

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.39
Sift	Benign	0.11	T
Sift4G	Benign	0.23	T
Polyphen		0.53	P
Vest4		0.081
MPC		0.072
ClinPred		0.013	T
GERP RS		5.9
Varity_R		0.15
gMVP		0.66
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61734789; hg19: chr7-16445813; COSMIC: COSV99063049;