2-178104312-G-A

Variant names:

• chr2-178104312-G-A
• rs75672043
• ENST00000358450.8:c.152C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001077197.2(PDE11A):​c.152C>T​(p.Thr51Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,612,882 control chromosomes in the GnomAD database, including 9,567 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. T51T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.091 (690 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8877 hom.)
• Consequence: PDE11A NM_001077197.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.29

Genes affected

PDE11A (HGNC:8773): (phosphodiesterase 11A) The 3',5'-cyclic nucleotides cAMP and cGMP function as second messengers in a wide variety of signal transduction pathways. 3',5'-cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP to the corresponding 5'-monophosphates and provide a mechanism to downregulate cAMP and cGMP signaling. This gene encodes a member of the PDE protein superfamily. Mutations in this gene are a cause of Cushing disease and adrenocortical hyperplasia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CYCTP (HGNC:24424): (cytochrome c, testis, pseudogene) Predicted to enable heme binding activity. Predicted to act upstream of or within hydrogen peroxide metabolic process and positive regulation of intrinsic apoptotic signaling pathway. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018588305).
• BP6: Variant 2-178104312-G-A is Benign according to our data. Variant chr2-178104312-G-A is described in ClinVar as [Benign]. Clinvar id is 3055903.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_001077197.2	c.152C>T	p.Thr51Ile	missense_variant	Exon 2 of 21		NP_001070665.1
CYCTP		n.178104312G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000358450.8	c.152C>T	p.Thr51Ile	missense_variant	Exon 2 of 21	1		ENSP00000351232.4
CYCTP	ENST00000504253.1	n.159C>T		non_coding_transcript_exon_variant	Exon 1 of 3	6

Frequencies

GnomAD3 genomes AF: 0.0906 AC: 13779 AN: 152014 Hom.: 690 Cov.: 32

Gnomad AFR AF: 0.0603

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0693

Gnomad ASJ AF: 0.0678

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0899

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0934

GnomAD3 exomes AF: 0.0916 AC: 22852 AN: 249524 Hom.: 1246 AF XY: 0.0951 AC XY: 12875 AN XY: 135366

Gnomad AFR exome AF: 0.0601

Gnomad AMR exome AF: 0.0550

Gnomad ASJ exome AF: 0.0712

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0911

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.107 AC: 156051 AN: 1460750 Hom.: 8877 Cov.: 31 AF XY: 0.107 AC XY: 77758 AN XY: 726752

Gnomad4 AFR exome AF: 0.0597

Gnomad4 AMR exome AF: 0.0589

Gnomad4 ASJ exome AF: 0.0705

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0922

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.0930

GnomAD4 genome AF: 0.0905 AC: 13775 AN: 152132 Hom.: 690 Cov.: 32 AF XY: 0.0903 AC XY: 6719 AN XY: 74396

Gnomad4 AFR AF: 0.0602

Gnomad4 AMR AF: 0.0691

Gnomad4 ASJ AF: 0.0678

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0896

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.0919

Alfa AF: 0.108 Hom.: 1512

Bravo AF: 0.0857

TwinsUK AF: 0.115 AC: 425

ALSPAC AF: 0.122 AC: 471

ESP6500AA AF: 0.0602 AC: 220

ESP6500EA AF: 0.114 AC: 931

ExAC AF: 0.0949 AC: 11468

Asia WGS AF: 0.0360 AC: 125 AN: 3478

EpiCase AF: 0.118

EpiControl AF: 0.119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PDE11A-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.2
DANN	Benign	0.89
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.079
Sift	Benign	0.057	T
Sift4G	Benign	0.17	T
Polyphen		0.61	P
Vest4		0.079
ClinPred		0.0090	T
GERP RS		1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs75672043; hg19: chr2-178969039;