10-35206973-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_183011.2(CREM):c.677C>T(p.Ser226Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00343 in 1,614,030 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (15 hom.)
• Consequence: CREM NM_183011.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.74

Genes affected

CREM (HGNC:2352): (cAMP responsive element modulator) This gene encodes a bZIP transcription factor that binds to the cAMP responsive element found in many viral and cellular promoters. It is an important component of cAMP-mediated signal transduction during the spermatogenetic cycle, as well as other complex processes. Alternative promoter and translation initiation site usage allows this gene to exert spatial and temporal specificity to cAMP responsiveness. Multiple alternatively spliced transcript variants encoding several different isoforms have been found for this gene, with some of them functioning as activators and some as repressors of transcription. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0105317235).
• BP6: Variant 10-35206973-C-T is Benign according to our data. Variant chr10-35206973-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 721155.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 360 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREM	NM_183011.2	c.677C>T	p.Ser226Leu	missense_variant	7/8	ENST00000685392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREM	ENST00000685392.1	c.677C>T	p.Ser226Leu	missense_variant	7/8		NM_183011.2	A1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 360 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00428

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00243 AC: 610 AN: 251460 Hom.: 2 AF XY: 0.00263 AC XY: 358 AN XY: 135900

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00468

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00354 AC: 5175 AN: 1461698 Hom.: 15 Cov.: 30 AF XY: 0.00345 AC XY: 2511 AN XY: 727156

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00436

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00236 AC: 360 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00231 AC XY: 172 AN XY: 74496

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00428

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00346 Hom.: 0

Bravo AF: 0.00236

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00279 AC: 339

EpiCase AF: 0.00458

EpiControl AF: 0.00468

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	0.00050	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;.;.;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	D;.;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D;.;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 0.99	.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;D;.;D;.;D;.;.;.;.;.;.
Vest4		0.81
MVP		0.59
MPC		0.48
ClinPred		0.043	T
GERP RS		5.8
Varity_R		0.44
gMVP		0.66

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: rs52806860; hg19: chr10-35495901; COSMIC: COSV99047413; COSMIC: COSV99047413;