rs2983521

Variant names:

• chr6-165643715-A-T
• rs2983521
• NM_001385079.1:c.865+18232T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001385079.1(PDE10A):​c.865+18232T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,176 control chromosomes in the GnomAD database, including 2,816 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2816 hom., cov: 32)
• Consequence: PDE10A NM_001385079.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.170
• Publications: 5 publications found

Genes affected

PDE10A (HGNC:8772): (phosphodiesterase 10A) The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase family. It plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This protein can hydrolyze both cAMP and cGMP to the corresponding nucleoside 5' monophosphate, but has higher affinity for cAMP, and is more efficient with cAMP as substrate. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2011]

PDE10A Gene-Disease associations (from GenCC):

• striatal degeneration, autosomal dominant 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dyskinesia, limb and orofacial, infantile-onset

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• infantile-onset generalized dyskinesia with orofacial involvement

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood-onset benign chorea with striatal involvement

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE10A	NM_001385079.1	c.865+18232T>A		intron_variant	Intron 1 of 21	ENST00000539869.4	NP_001372008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE10A	ENST00000539869.4	c.865+18232T>A		intron_variant	Intron 1 of 21	1	NM_001385079.1	ENSP00000438284.3

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27318 AN: 152058 Hom.: 2815 Cov.: 32

Gnomad AFR AF: 0.0918

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.00617

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.211

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.180 AC: 27318 AN: 152176 Hom.: 2816 Cov.: 32 AF XY: 0.180 AC XY: 13380 AN XY: 74404

African (AFR) AF: 0.0918 AC: 3813 AN: 41540

American (AMR) AF: 0.177 AC: 2699 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 938 AN: 3472

East Asian (EAS) AF: 0.00619 AC: 32 AN: 5172

South Asian (SAS) AF: 0.213 AC: 1026 AN: 4820

European-Finnish (FIN) AF: 0.213 AC: 2259 AN: 10598

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15747 AN: 67972

Other (OTH) AF: 0.213 AC: 449 AN: 2110

Alfa AF: 0.201 Hom.: 435

Bravo AF: 0.173

Asia WGS AF: 0.119 AC: 413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.0
DANN	Benign	0.75
PhyloP100		-0.17

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

Other links and lift over

dbSNP: rs2983521; hg19: chr6-166057203; COSMIC: COSV64840552;