12-93850168-GT-CC

Variant names:

• chr12-93850168-GT-CC
• NM_003805.5:c.497_498delGTinsCC
• CRADD p.Arg166Pro

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_003805.5(CRADD):​c.497_498delGTinsCC​(p.Arg166Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R166H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRADD NM_003805.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• Publications: 0 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, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_003805.5

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRADD	NM_003805.5	MANE Select	c.497_498delGTinsCC	p.Arg166Pro	missense	N/A	NP_003796.1	P78560-1
	CRADD	NM_001320099.2		c.497_498delGTinsCC	p.Arg166Pro	missense	N/A	NP_001307028.1	P78560-1
	CRADD	NM_001320100.2		c.299-43882_299-43881delGTinsCC		intron	N/A	NP_001307029.1	F5H7C2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRADD	ENST00000332896.8	TSL:1 MANE Select	c.497_498delGTinsCC	p.Arg166Pro	missense	N/A	ENSP00000327647.3	P78560-1
	CRADD	ENST00000542893.2	TSL:1	c.497_498delGTinsCC	p.Arg166Pro	missense	N/A	ENSP00000439068.2	P78560-1
	CRADD	ENST00000880420.1		c.497_498delGTinsCC	p.Arg166Pro	missense	N/A	ENSP00000550479.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-94243944;