chr2-177817928-A-G

Variant names:

• chr2-177817928-A-G
• rs3821010
• NM_016953.4:c.1577-3T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016953.4(PDE11A):​c.1577-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 1,396,904 control chromosomes in the GnomAD database, including 75,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14371 hom., cov: 31)
  • Exomes 𝑓: 0.31 (61075 hom.)
• Consequence: PDE11A NM_016953.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004978
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.41
• Publications: 18 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]

PDE11A Gene-Disease associations (from GenCC):

• pigmented nodular adrenocortical disease, primary, 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine
• primary pigmented nodular adrenocortical disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-177817928-A-G is Benign according to our data. Variant chr2-177817928-A-G is described in ClinVar as [Benign]. Clinvar id is 1327001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.1577-3T>C		splice_region_variant, intron_variant	Intron 7 of 19	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2	c.827-3T>C		splice_region_variant, intron_variant	Intron 8 of 20		NP_001070665.1
PDE11A	NM_001077358.2	c.503-3T>C		splice_region_variant, intron_variant	Intron 6 of 18		NP_001070826.1
PDE11A	NM_001077196.2	c.245-3T>C		splice_region_variant, intron_variant	Intron 4 of 16		NP_001070664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.1577-3T>C		splice_region_variant, intron_variant	Intron 7 of 19	1	NM_016953.4	ENSP00000286063.5

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61646 AN: 151786 Hom.: 14355 Cov.: 31

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.324 AC: 81066 AN: 250122 AF XY: 0.325

Gnomad AFR exome AF: 0.648

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.314

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.305 AC: 380217 AN: 1245000 Hom.: 61075 Cov.: 20 AF XY: 0.308 AC XY: 194133 AN XY: 630134

African (AFR) AF: 0.640 AC: 17523 AN: 27366

American (AMR) AF: 0.219 AC: 9728 AN: 44406

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 9182 AN: 24620

East Asian (EAS) AF: 0.298 AC: 11528 AN: 38644

South Asian (SAS) AF: 0.335 AC: 27409 AN: 81762

European-Finnish (FIN) AF: 0.238 AC: 12646 AN: 53038

Middle Eastern (MID) AF: 0.411 AC: 2172 AN: 5288

European-Non Finnish (NFE) AF: 0.297 AC: 272703 AN: 916994

Other (OTH) AF: 0.328 AC: 17326 AN: 52882

GnomAD4 genome AF: 0.406 AC: 61704 AN: 151904 Hom.: 14371 Cov.: 31 AF XY: 0.400 AC XY: 29705 AN XY: 74254

African (AFR) AF: 0.644 AC: 26661 AN: 41394

American (AMR) AF: 0.310 AC: 4728 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1336 AN: 3466

East Asian (EAS) AF: 0.319 AC: 1643 AN: 5152

South Asian (SAS) AF: 0.332 AC: 1598 AN: 4816

European-Finnish (FIN) AF: 0.235 AC: 2479 AN: 10556

Middle Eastern (MID) AF: 0.428 AC: 124 AN: 290

European-Non Finnish (NFE) AF: 0.321 AC: 21777 AN: 67942

Other (OTH) AF: 0.417 AC: 880 AN: 2108

Alfa AF: 0.355 Hom.: 20250

Bravo AF: 0.422

Asia WGS AF: 0.297 AC: 1035 AN: 3478

EpiCase AF: 0.339

EpiControl AF: 0.347

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pigmented nodular adrenocortical disease, primary, 2 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.7
DANN	Benign	0.69
PhyloP100		1.4
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs3821010; hg19: chr2-178682655; COSMIC: COSV53695596;