7-137885072-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_194071.4(CREB3L2):c.1193A>G(p.Tyr398Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CREB3L2 NM_194071.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.419

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15381145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREB3L2	NM_194071.4	c.1193A>G	p.Tyr398Cys	missense_variant	10/12	ENST00000330387.11
CREB3L2	NM_001318246.2	c.1004A>G	p.Tyr335Cys	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREB3L2	ENST00000330387.11	c.1193A>G	p.Tyr398Cys	missense_variant	10/12	1	NM_194071.4	P1
CREB3L2	ENST00000456390.5	c.1193A>G	p.Tyr398Cys	missense_variant	10/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.1193A>G (p.Y398C) alteration is located in exon 10 (coding exon 10) of the CREB3L2 gene. This alteration results from a A to G substitution at nucleotide position 1193, causing the tyrosine (Y) at amino acid position 398 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.65	D;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.063
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.051	T;D
Polyphen		0.38	B;P
Vest4		0.40
MutPred		0.36		Loss of disorder (P = 0.0929);Loss of disorder (P = 0.0929);
MVP		0.36
MPC		0.17
ClinPred		0.58	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs1300445623; hg19: chr7-137569818;