12-93759028-T-C

Variant names:

• chr12-93759028-T-C
• rs1493848
• NM_003805.5:c.298+79956T>C

Variant summary

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

The NM_003805.5(CRADD):​c.298+79956T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 152,042 control chromosomes in the GnomAD database, including 10,928 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 0.35 (10928 hom., cov: 32)
• Consequence: CRADD NM_003805.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• Publications: 6 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=-0.52).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 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.298+79956T>C		intron	N/A	NP_003796.1
	CRADD	NM_001320099.2		c.298+79956T>C		intron	N/A	NP_001307028.1
	CRADD	NM_001320100.2		c.298+79956T>C		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.298+79956T>C		intron	N/A	ENSP00000327647.3
	CRADD	ENST00000542893.2	TSL:1	c.298+79956T>C		intron	N/A	ENSP00000439068.2
	CRADD	ENST00000548483.5	TSL:2	c.298+79956T>C		intron	N/A	ENSP00000448685.1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53794 AN: 151924 Hom.: 10920 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.365

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

GnomAD4 genome AF: 0.354 AC: 53819 AN: 152042 Hom.: 10928 Cov.: 32 AF XY: 0.358 AC XY: 26622 AN XY: 74314

African (AFR) AF: 0.157 AC: 6519 AN: 41508

American (AMR) AF: 0.377 AC: 5749 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1171 AN: 3466

East Asian (EAS) AF: 0.605 AC: 3129 AN: 5170

South Asian (SAS) AF: 0.567 AC: 2734 AN: 4818

European-Finnish (FIN) AF: 0.422 AC: 4457 AN: 10562

Middle Eastern (MID) AF: 0.346 AC: 101 AN: 292

European-Non Finnish (NFE) AF: 0.424 AC: 28777 AN: 67944

Other (OTH) AF: 0.368 AC: 777 AN: 2110

Alfa AF: 0.405 Hom.: 15244

Bravo AF: 0.337

Asia WGS AF: 0.524 AC: 1815 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.78
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1493848; hg19: chr12-94152804;