7-16258450-C-T

Variant names:

• chr7-16258450-C-T
• rs181099904
• NM_001101426.4:c.1059G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001101426.4(CRPPA):​c.1059G>A​(p.Lys353Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,604,880 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: CRPPA NM_001101426.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.821
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 7-16258450-C-T is Benign according to our data. Variant chr7-16258450-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198765.
• BP7: Synonymous conserved (PhyloP=-0.821 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.1059G>A	p.Lys353Lys	synonymous	Exon 8 of 10	NP_001094896.1	A4D126-1
	CRPPA	NM_001368197.1		c.954G>A	p.Lys318Lys	synonymous	Exon 7 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.909G>A	p.Lys303Lys	synonymous	Exon 7 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.1059G>A	p.Lys353Lys	synonymous	Exon 8 of 10	ENSP00000385478.2	A4D126-1
	CRPPA	ENST00000399310.3	TSL:1	c.909G>A	p.Lys303Lys	synonymous	Exon 7 of 9	ENSP00000382249.3	A4D126-2
	CRPPA-AS1	ENST00000438573.5	TSL:1	n.222-3449C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00136 AC: 327 AN: 240028 AF XY: 0.00144

Gnomad AFR exome AF: 0.000136

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.000616

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000521

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.00245 AC: 3559 AN: 1452716 Hom.: 9 Cov.: 29 AF XY: 0.00242 AC XY: 1749 AN XY: 722336

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000241 AC: 8 AN: 33148

American (AMR) AF: 0.000114 AC: 5 AN: 43720

Ashkenazi Jewish (ASJ) AF: 0.000580 AC: 15 AN: 25862

East Asian (EAS) AF: 0.00 AC: 0 AN: 39350

South Asian (SAS) AF: 0.000248 AC: 21 AN: 84718

European-Finnish (FIN) AF: 0.000793 AC: 42 AN: 52946

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5744

European-Non Finnish (NFE) AF: 0.00305 AC: 3381 AN: 1107244

Other (OTH) AF: 0.00142 AC: 85 AN: 59984

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74410

African (AFR) AF: 0.000457 AC: 19 AN: 41554

American (AMR) AF: 0.000197 AC: 3 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00232 AC: 158 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00139

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	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
BayesDel_noAF	Benign	-0.59
CADD	Benign	3.2
DANN	Benign	0.76
PhyloP100		-0.82
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs181099904; hg19: chr7-16298075;