7-137885091-C-A

Variant names:

• chr7-137885091-C-A
• rs1464565998
• NM_194071.4:c.1174G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_194071.4(CREB3L2):​c.1174G>T​(p.Gly392Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G392R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CREB3L2 NM_194071.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.19
• Publications: 0 publications found

Genes affected

CREB3L2 (HGNC:23720): (cAMP responsive element binding protein 3 like 2) This gene encodes a member of the oasis bZIP transcription factor family. Members of this family can dimerize but form homodimers only. The encoded protein is a transcriptional activator. Translocations between this gene on chromosome 7 and the gene fused in sarcoma on chromosome 16 can be found in some tumors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194071.4. 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
	CREB3L2	NM_194071.4	MANE Select	c.1174G>T	p.Gly392Cys	missense	Exon 10 of 12	NP_919047.2	Q70SY1-1
	CREB3L2	NM_001318246.2		c.985G>T	p.Gly329Cys	missense	Exon 10 of 12	NP_001305175.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB3L2	ENST00000330387.11	TSL:1 MANE Select	c.1174G>T	p.Gly392Cys	missense	Exon 10 of 12	ENSP00000329140.6	Q70SY1-1
	CREB3L2	ENST00000898368.1		c.1168G>T	p.Gly390Cys	missense	Exon 10 of 12	ENSP00000568427.1
	CREB3L2	ENST00000456390.5	TSL:2	c.1174G>T	p.Gly392Cys	missense	Exon 10 of 10	ENSP00000403550.1	Q70SY1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

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

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.66		Gain of catalytic residue at G392 (P = 0.0851)
MVP		0.87
MPC		0.52
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.55
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1464565998; hg19: chr7-137569837;