rs114363936

Variant names:

• chr7-16258999-G-T
• rs114363936
• NM_001101426.4:c.947C>A

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.947C>A​(p.Thr316Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,609,120 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T316T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0065 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (12 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.210
• Publications: 2 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-AS1 (HGNC:48962): (CRPPA antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008729011).
• BP6: Variant 7-16258999-G-T is Benign according to our data. Variant chr7-16258999-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00653 (993/152088) while in subpopulation AFR AF = 0.0225 (936/41518). AF 95% confidence interval is 0.0213. There are 12 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.947C>A	p.Thr316Lys	missense	Exon 7 of 10	NP_001094896.1	A4D126-1
	CRPPA	NM_001368197.1		c.842C>A	p.Thr281Lys	missense	Exon 6 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.797C>A	p.Thr266Lys	missense	Exon 6 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.947C>A	p.Thr316Lys	missense	Exon 7 of 10	ENSP00000385478.2	A4D126-1
	CRPPA	ENST00000399310.3	TSL:1	c.797C>A	p.Thr266Lys	missense	Exon 6 of 9	ENSP00000382249.3	A4D126-2
	CRPPA-AS1	ENST00000438573.5	TSL:1	n.222-2900G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 993 AN: 151970 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00150 AC: 367 AN: 244720 AF XY: 0.00115

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000811

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000640 AC: 932 AN: 1457032 Hom.: 12 Cov.: 29 AF XY: 0.000553 AC XY: 401 AN XY: 724740

African (AFR) AF: 0.0214 AC: 712 AN: 33306

American (AMR) AF: 0.00150 AC: 66 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.0000584 AC: 5 AN: 85590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5752

European-Non Finnish (NFE) AF: 0.0000343 AC: 38 AN: 1109346

Other (OTH) AF: 0.00166 AC: 100 AN: 60146

GnomAD4 genome AF: 0.00653 AC: 993 AN: 152088 Hom.: 12 Cov.: 33 AF XY: 0.00617 AC XY: 459 AN XY: 74338

African (AFR) AF: 0.0225 AC: 936 AN: 41518

American (AMR) AF: 0.00229 AC: 35 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67920

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00211 Hom.: 5

Bravo AF: 0.00757

ESP6500AA AF: 0.0197 AC: 76

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00185 AC: 223

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000120

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U (2)
-	-	1	Congenital Muscular Dystrophy, alpha-dystroglycan related (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.21
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.28
Sift	Uncertain	0.014	D
Sift4G	Benign	0.57	T
Polyphen		0.87	P
Vest4		0.40
MVP		0.50
MPC		0.067
ClinPred		0.0067	T
GERP RS		0.23
Varity_R		0.14
gMVP		0.53
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs114363936; hg19: chr7-16298624; COSMIC: COSV99063057;