chr11-46300016-C-T

Variant names:

• chr11-46300016-C-T
• NM_052854.4:c.184C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_052854.4(CREB3L1):​c.184C>T​(p.Pro62Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CREB3L1 NM_052854.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98
• Publications: 0 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.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052854.4. 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.184C>T	p.Pro62Ser	missense	Exon 2 of 12	NP_443086.1	Q96BA8-1
	CREB3L1	NM_001425266.1		c.184C>T	p.Pro62Ser	missense	Exon 2 of 12	NP_001412195.1
	CREB3L1	NM_001425267.1		c.184C>T	p.Pro62Ser	missense	Exon 2 of 12	NP_001412196.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB3L1	ENST00000621158.5	TSL:1 MANE Select	c.184C>T	p.Pro62Ser	missense	Exon 2 of 12	ENSP00000481956.1	Q96BA8-1
	CREB3L1	ENST00000862985.1		c.184C>T	p.Pro62Ser	missense	Exon 2 of 12	ENSP00000533044.1
	CREB3L1	ENST00000862986.1		c.184C>T	p.Pro62Ser	missense	Exon 2 of 10	ENSP00000533045.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461662 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111838

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0095	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.25
MutPred		0.25		Gain of phosphorylation at P62 (P = 0.0261)
MVP		0.64
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.29
Mutation Taster		=46/54	disease causing

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

hg19: chr11-46321567;