rs202117698

Variant names:

• chr2-178104442-GTC-G
• rs202117698
• ENST00000358450.8:c.20_21delGA

Your query was ambiguous. Multiple possible variants found:

• chr2-178104442-GTC-G
• chr2-178104442-GTC-GTCTC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_Strong BS1_Supporting BS2

The NM_001077197.2(PDE11A):​c.20_21delGA​(p.Arg7ThrfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,614,002 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (8 hom.)
• Consequence: PDE11A NM_001077197.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:1
• Conservation: PhyloP100: 1.86
• Publications: 11 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00258 (392/152228) while in subpopulation NFE AF = 0.00288 (196/68018). AF 95% confidence interval is 0.00255. There are 0 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 392 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077197.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE11A	NM_001077197.2		c.20_21delGA	p.Arg7ThrfsTer30	frameshift	Exon 2 of 21	NP_001070665.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE11A	ENST00000358450.8	TSL:1	c.20_21delGA	p.Arg7ThrfsTer30	frameshift	Exon 2 of 21	ENSP00000351232.4
	CYCTP	ENST00000504253.1	TSL:6	n.27_28delGA		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 392 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00305 AC: 760 AN: 249534 AF XY: 0.00299

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00300

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00291 AC: 4258 AN: 1461774 Hom.: 8 AF XY: 0.00286 AC XY: 2078 AN XY: 727188

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.000850 AC: 38 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26132

East Asian (EAS) AF: 0.00189 AC: 75 AN: 39680

South Asian (SAS) AF: 0.00108 AC: 93 AN: 86250

European-Finnish (FIN) AF: 0.0137 AC: 733 AN: 53414

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.00279 AC: 3106 AN: 1111938

Other (OTH) AF: 0.00252 AC: 152 AN: 60392

GnomAD4 genome AF: 0.00258 AC: 392 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00292 AC XY: 217 AN XY: 74422

African (AFR) AF: 0.000554 AC: 23 AN: 41540

American (AMR) AF: 0.000458 AC: 7 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5188

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4814

European-Finnish (FIN) AF: 0.0123 AC: 130 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68018

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000678 Hom.: 0

Bravo AF: 0.00162

EpiCase AF: 0.00267

EpiControl AF: 0.00261

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Pigmented nodular adrenocortical disease, primary, 2 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=156/44	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs202117698; hg19: chr2-178969169; COSMIC: COSV61771728; COSMIC: COSV61771728;