NM_003805.5:c.299-7900G>A

Variant names:

• chr12-93842070-G-A
• rs12308959
• NM_003805.5:c.299-7900G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003805.5(CRADD):​c.299-7900G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 151,964 control chromosomes in the GnomAD database, including 16,334 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 0.46 (16334 hom., cov: 32)
• Consequence: CRADD NM_003805.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.651
• Publications: 4 publications found

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, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.664 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRADD	NM_003805.5	MANE Select	c.299-7900G>A		intron	N/A	NP_003796.1
	CRADD	NM_001320099.2		c.299-7900G>A		intron	N/A	NP_001307028.1
	CRADD	NM_001320100.2		c.299-51980G>A		intron	N/A	NP_001307029.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRADD	ENST00000332896.8	TSL:1 MANE Select	c.299-7900G>A		intron	N/A	ENSP00000327647.3
	CRADD	ENST00000542893.2	TSL:1	c.299-7900G>A		intron	N/A	ENSP00000439068.2
	CRADD	ENST00000548483.5	TSL:2	c.299-51980G>A		intron	N/A	ENSP00000448685.1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69840 AN: 151846 Hom.: 16319 Cov.: 32

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.472

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

GnomAD4 genome AF: 0.460 AC: 69888 AN: 151964 Hom.: 16334 Cov.: 32 AF XY: 0.458 AC XY: 33996 AN XY: 74300

African (AFR) AF: 0.458 AC: 18973 AN: 41412

American (AMR) AF: 0.432 AC: 6595 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1571 AN: 3466

East Asian (EAS) AF: 0.683 AC: 3528 AN: 5168

South Asian (SAS) AF: 0.409 AC: 1972 AN: 4820

European-Finnish (FIN) AF: 0.403 AC: 4252 AN: 10552

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.462 AC: 31420 AN: 67964

Other (OTH) AF: 0.477 AC: 1006 AN: 2108

Alfa AF: 0.465 Hom.: 34926

Bravo AF: 0.463

Asia WGS AF: 0.550 AC: 1913 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	1.1
DANN	Benign	0.48
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12308959; hg19: chr12-94235846;