NM_016302.4:c.688-1670T>G

Variant names:

• chr3-3157951-A-C
• rs1669338
• NM_016302.4:c.688-1670T>G

Variant summary

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

The NM_016302.4(CRBN):​c.688-1670T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 152,084 control chromosomes in the GnomAD database, including 42,005 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 0.72 (42005 hom., cov: 31)
• Consequence: CRBN NM_016302.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265
• Publications: 12 publications found

Genes affected

CRBN (HGNC:30185): (cereblon) This gene encodes a protein related to the Lon protease protein family. In rodents and other mammals this gene product is found in the cytoplasm localized with a calcium channel membrane protein, and is thought to play a role in brain development. Mutations in this gene are associated with autosomal recessive nonsyndromic cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

CRBN Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal recessive 2

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

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 (EAS) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016302.4. 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
	CRBN	NM_016302.4	MANE Select	c.688-1670T>G		intron	N/A	NP_057386.2
	CRBN	NM_001173482.1		c.685-1670T>G		intron	N/A	NP_001166953.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRBN	ENST00000231948.9	TSL:1 MANE Select	c.688-1670T>G		intron	N/A	ENSP00000231948.4
	CRBN	ENST00000432408.6	TSL:1	c.685-1670T>G		intron	N/A	ENSP00000412499.2
	CRBN	ENST00000491834.5	TSL:1	n.585-1670T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109517 AN: 151966 Hom.: 42007 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.893

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.851

Gnomad EAS AF: 0.920

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.830

Gnomad MID AF: 0.844

Gnomad NFE AF: 0.836

Gnomad OTH AF: 0.764

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

GnomAD4 genome AF: 0.720 AC: 109537 AN: 152084 Hom.: 42005 Cov.: 31 AF XY: 0.725 AC XY: 53887 AN XY: 74344

African (AFR) AF: 0.429 AC: 17797 AN: 41476

American (AMR) AF: 0.769 AC: 11748 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.851 AC: 2950 AN: 3468

East Asian (EAS) AF: 0.920 AC: 4756 AN: 5172

South Asian (SAS) AF: 0.834 AC: 4013 AN: 4814

European-Finnish (FIN) AF: 0.830 AC: 8787 AN: 10588

Middle Eastern (MID) AF: 0.842 AC: 246 AN: 292

European-Non Finnish (NFE) AF: 0.836 AC: 56811 AN: 67974

Other (OTH) AF: 0.765 AC: 1615 AN: 2110

Alfa AF: 0.794 Hom.: 161067

Bravo AF: 0.699

Asia WGS AF: 0.837 AC: 2913 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	1.3
DANN	Benign	0.78
PhyloP100		-0.27
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: rs1669338; hg19: chr3-3199635;