Genetic Variant CRADD:c.299-8581A>G (chr12-93841389-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003805.5(CRADD):c.299-8581A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 152,256 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.041 ( 156 hom., cov: 32)

Consequence

CRADD
NM_003805.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0540

Publications

12 publications found

Variant links:

Genes affected

CRADD (HGNC:2340): (CASP2 and RIPK1 domain containing adaptor with death domain) This gene encodes a protein containing a death domain (DD) motif. This protein recruits caspase 2/ICH1 to the cell death signal transduction complex, which includes tumor necrosis factor receptor 1 (TNFR1A) and RIPK1/RIP kinase, and acts in promoting apoptosis. A mutation in this gene was associated with cognitive disability. A related pseudogene is found on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

CRADD Gene-Disease associations (from GenCC):

syndromic intellectual disability
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, autosomal recessive 34
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CRADD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003805.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CRADD	NM_003805.5	MANE Select	c.299-8581A>G	intron	N/A	NP_003796.1	P78560-1
CRADD	NM_001320099.2		c.299-8581A>G	intron	N/A	NP_001307028.1	P78560-1
CRADD	NM_001320100.2		c.299-52661A>G	intron	N/A	NP_001307029.1	F5H7C2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CRADD	ENST00000332896.8	TSL:1 MANE Select	c.299-8581A>G	intron	N/A	ENSP00000327647.3	P78560-1
CRADD	ENST00000542893.2	TSL:1	c.299-8581A>G	intron	N/A	ENSP00000439068.2	P78560-1
CRADD	ENST00000880420.1		c.299-8581A>G	intron	N/A	ENSP00000550479.1

Frequencies

GnomAD3 genomes

AF:

0.0407

AC:

6192

AN:

152138

Hom.:

155

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0265

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0774

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.0304

Gnomad SAS

AF:

0.0608

Gnomad FIN

AF:

0.0495

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0388

Gnomad OTH

AF:

0.0425

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0407

AC:

6201

AN:

152256

Hom.:

156

Cov.:

AF XY:

0.0422

AC XY:

3144

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0265

AC:

1099

AN:

41534

American (AMR)

AF:

0.0778

AC:

1190

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

178

AN:

3468

East Asian (EAS)

AF:

0.0305

AC:

158

AN:

5186

South Asian (SAS)

AF:

0.0611

AC:

295

AN:

4828

European-Finnish (FIN)

AF:

0.0495

AC:

524

AN:

10596

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0388

AC:

2639

AN:

68028

Other (OTH)

AF:

0.0421

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

295

590

886

1181

1476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0404

Hom.:

231

Bravo

AF:

0.0416

Asia WGS

AF:

0.0510

AC:

178

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.5

(source)

DANN

Benign

0.58

PhyloP100

0.054

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over