12-93887376-C-T

Variant names:

• chr12-93887376-C-T
• rs10507027
• NM_001320100.2:c.299-6674C>T

Variant summary

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

The NM_001320100.2(CRADD):​c.299-6674C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0499 in 152,128 control chromosomes in the GnomAD database, including 435 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 0.050 (435 hom., cov: 33)
• Consequence: CRADD NM_001320100.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.428
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320100.2. 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_001320100.2		c.299-6674C>T		intron	N/A	NP_001307029.1	F5H7C2
	CRADD	NR_135147.2		n.527-6674C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRADD	ENST00000548483.5	TSL:2	c.299-6674C>T		intron	N/A	ENSP00000448685.1	F5H7C2
	CRADD	ENST00000551065.5	TSL:2	n.*111-6674C>T		intron	N/A	ENSP00000448425.1	P78560-2

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7549 AN: 152010 Hom.: 429 Cov.: 33

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.0731

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00609

Gnomad OTH AF: 0.0375

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

GnomAD4 genome AF: 0.0499 AC: 7586 AN: 152128 Hom.: 435 Cov.: 33 AF XY: 0.0514 AC XY: 3825 AN XY: 74368

African (AFR) AF: 0.130 AC: 5397 AN: 41472

American (AMR) AF: 0.0226 AC: 345 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.122 AC: 634 AN: 5186

South Asian (SAS) AF: 0.0736 AC: 354 AN: 4810

European-Finnish (FIN) AF: 0.0303 AC: 320 AN: 10568

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00609 AC: 414 AN: 68018

Other (OTH) AF: 0.0413 AC: 87 AN: 2104

Alfa AF: 0.0183 Hom.: 218

Bravo AF: 0.0518

Asia WGS AF: 0.102 AC: 356 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.40
DANN	Benign	0.67
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10507027; hg19: chr12-94281152;