11-46320708-AG-AGG

Variant names:

• chr11-46320708-A-AG
• rs79068197
• NM_052854.4:c.1525dupG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 10P and 8B. PVS1 PM2 BP6_Very_Strong

The ENST00000621158.5(CREB3L1):​c.1524-2_1524-1insG variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CREB3L1 ENST00000621158.5 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.25
• Publications: 14 publications found

Genes affected

CREB3L1 (HGNC:18856): (cAMP responsive element binding protein 3 like 1) The protein encoded by this gene is normally found in the membrane of the endoplasmic reticulum (ER). However, upon stress to the ER, the encoded protein is cleaved and the released cytoplasmic transcription factor domain translocates to the nucleus. There it activates the transcription of target genes by binding to box-B elements. [provided by RefSeq, Jun 2013]

CREB3L1 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 16

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 11, offset of -1, new splice context is: ggcctctcttctctctccAGggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-46320708-A-AG is Benign according to our data. Variant chr11-46320708-A-AG is described in ClinVar as Benign. ClinVar VariationId is 402564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000621158.5. 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
	CREB3L1	NM_052854.4	MANE Select	c.1525dupG	p.Asp509fs	frameshift splice_region	Exon 12 of 12	NP_443086.1	Q96BA8-1
	CREB3L1	NM_001425267.1		c.1519dupG	p.Asp507fs	frameshift splice_region	Exon 12 of 12	NP_001412196.1
	CREB3L1	NM_001425268.1		c.1387dupG	p.Asp463fs	frameshift splice_region	Exon 12 of 12	NP_001412197.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB3L1	ENST00000621158.5	TSL:1 MANE Select	c.1524-2_1524-1insG		splice_acceptor intron	N/A	ENSP00000481956.1	Q96BA8-1
	CREB3L1	ENST00000616094.1	TSL:1	n.1118-2_1118-1insG		splice_acceptor intron	N/A
	CREB3L1	ENST00000862985.1		c.1500-2_1500-1insG		splice_acceptor intron	N/A	ENSP00000533044.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 1.00 AC: 245281 AN: 245288 AF XY: 1.00

Gnomad AFR exome AF: 1.00

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 1.00 Hom.: 6765

Asia WGS AF: 1.00 AC: 3475 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Osteogenesis imperfecta type 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2

Splicing

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

Other links and lift over

dbSNP: rs79068197; hg19: chr11-46342259; COSMIC: COSV55830359; COSMIC: COSV55830359;