2-177669596-A-G

Variant names:

• chr2-177669596-A-G
• rs6433687
• NM_016953.4:c.2488-29T>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.2488-29T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.858 in 1,009,858 control chromosomes in the GnomAD database, including 373,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.81 (50934 hom., cov: 33)
  • Exomes 𝑓: 0.87 (322678 hom.)
• Consequence: PDE11A NM_016953.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09
• Publications: 14 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-AS1 (HGNC:40433): (PDE11A antisense RNA 1)

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-177669596-A-G is Benign according to our data. Variant chr2-177669596-A-G is described in ClinVar as Benign. ClinVar VariationId is 1326997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_016953.4	c.2488-29T>C		intron_variant	Intron 17 of 19	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2	c.1738-29T>C		intron_variant	Intron 18 of 20		NP_001070665.1
PDE11A	NM_001077358.2	c.1414-29T>C		intron_variant	Intron 16 of 18		NP_001070826.1
PDE11A	NM_001077196.2	c.1156-29T>C		intron_variant	Intron 14 of 16		NP_001070664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11	c.2488-29T>C		intron_variant	Intron 17 of 19	1	NM_016953.4	ENSP00000286063.5

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123501 AN: 152112 Hom.: 50903 Cov.: 33

Gnomad AFR AF: 0.659

Gnomad AMI AF: 0.947

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.978

Gnomad SAS AF: 0.896

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.816

GnomAD2 exomes AF: 0.865 AC: 215458 AN: 249004 AF XY: 0.868

Gnomad AFR exome AF: 0.650

Gnomad AMR exome AF: 0.918

Gnomad ASJ exome AF: 0.810

Gnomad EAS exome AF: 0.982

Gnomad FIN exome AF: 0.889

Gnomad NFE exome AF: 0.854

Gnomad OTH exome AF: 0.856

GnomAD4 exome AF: 0.866 AC: 742557 AN: 857628 Hom.: 322678 Cov.: 11 AF XY: 0.867 AC XY: 392112 AN XY: 452196

African (AFR) AF: 0.653 AC: 14367 AN: 21990

American (AMR) AF: 0.913 AC: 40193 AN: 44006

Ashkenazi Jewish (ASJ) AF: 0.812 AC: 18179 AN: 22400

East Asian (EAS) AF: 0.988 AC: 36560 AN: 37010

South Asian (SAS) AF: 0.895 AC: 66363 AN: 74110

European-Finnish (FIN) AF: 0.886 AC: 45549 AN: 51396

Middle Eastern (MID) AF: 0.860 AC: 3973 AN: 4618

European-Non Finnish (NFE) AF: 0.860 AC: 482802 AN: 561470

Other (OTH) AF: 0.851 AC: 34571 AN: 40628

GnomAD4 genome AF: 0.812 AC: 123591 AN: 152230 Hom.: 50934 Cov.: 33 AF XY: 0.816 AC XY: 60769 AN XY: 74434

African (AFR) AF: 0.659 AC: 27357 AN: 41504

American (AMR) AF: 0.873 AC: 13346 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2798 AN: 3472

East Asian (EAS) AF: 0.977 AC: 5071 AN: 5188

South Asian (SAS) AF: 0.896 AC: 4327 AN: 4828

European-Finnish (FIN) AF: 0.887 AC: 9416 AN: 10610

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.859 AC: 58432 AN: 68014

Other (OTH) AF: 0.818 AC: 1729 AN: 2114

Alfa AF: 0.829 Hom.: 18372

Bravo AF: 0.801

Asia WGS AF: 0.912 AC: 3169 AN: 3478

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	-0.88
CADD	Benign	1.0
DANN	Benign	0.19
PhyloP100		-1.1
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6433687; hg19: chr2-178534324;