chr6-165418739-C-T

Variant names:

• chr6-165418739-C-T
• rs220740
• NM_001385079.1:c.1692G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001385079.1(PDE10A):​c.1692G>A​(p.Ala564Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,611,826 control chromosomes in the GnomAD database, including 61,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7296 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54554 hom.)
• Consequence: PDE10A NM_001385079.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.744
• Publications: 13 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dyskinesia, limb and orofacial, infantile-onset

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 6-165418739-C-T is Benign according to our data. Variant chr6-165418739-C-T is described in ClinVar as Benign. ClinVar VariationId is 1164211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.744 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385079.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE10A	NM_001385079.1	MANE Select	c.1692G>A	p.Ala564Ala	synonymous	Exon 11 of 22	NP_001372008.1	Q9Y233-3
	PDE10A	NM_001130690.3		c.894G>A	p.Ala298Ala	synonymous	Exon 11 of 22	NP_001124162.1	Q9Y233-2
	PDE10A	NM_006661.4		c.864G>A	p.Ala288Ala	synonymous	Exon 12 of 23	NP_006652.1	A0A1B1UZR0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE10A	ENST00000539869.4	TSL:1 MANE Select	c.1692G>A	p.Ala564Ala	synonymous	Exon 11 of 22	ENSP00000438284.3	Q9Y233-3
	PDE10A	ENST00000647768.3		c.1068G>A	p.Ala356Ala	synonymous	Exon 12 of 23	ENSP00000497930.3	A0A3B3ITT8
	PDE10A	ENST00000672902.1		c.945G>A	p.Ala315Ala	synonymous	Exon 12 of 23	ENSP00000500351.1	A0A5F9ZHF9

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45439 AN: 151782 Hom.: 7289 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.0913

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.310

GnomAD2 exomes AF: 0.252 AC: 63168 AN: 250980 AF XY: 0.255

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.0954

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.287

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.267 AC: 389863 AN: 1459926 Hom.: 54554 Cov.: 32 AF XY: 0.266 AC XY: 193558 AN XY: 726388

African (AFR) AF: 0.414 AC: 13837 AN: 33444

American (AMR) AF: 0.158 AC: 7058 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 10133 AN: 26114

East Asian (EAS) AF: 0.0856 AC: 3399 AN: 39696

South Asian (SAS) AF: 0.214 AC: 18444 AN: 86212

European-Finnish (FIN) AF: 0.229 AC: 12160 AN: 53190

Middle Eastern (MID) AF: 0.404 AC: 2326 AN: 5764

European-Non Finnish (NFE) AF: 0.275 AC: 305705 AN: 1110474

Other (OTH) AF: 0.279 AC: 16801 AN: 60324

GnomAD4 genome AF: 0.299 AC: 45475 AN: 151900 Hom.: 7296 Cov.: 32 AF XY: 0.295 AC XY: 21898 AN XY: 74226

African (AFR) AF: 0.404 AC: 16734 AN: 41394

American (AMR) AF: 0.221 AC: 3368 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1312 AN: 3470

East Asian (EAS) AF: 0.0919 AC: 476 AN: 5178

South Asian (SAS) AF: 0.203 AC: 977 AN: 4810

European-Finnish (FIN) AF: 0.228 AC: 2401 AN: 10530

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19245 AN: 67942

Other (OTH) AF: 0.313 AC: 660 AN: 2112

Alfa AF: 0.286 Hom.: 14148

Bravo AF: 0.305

Asia WGS AF: 0.185 AC: 643 AN: 3478

EpiCase AF: 0.301

EpiControl AF: 0.311

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Infantile-onset generalized dyskinesia with orofacial involvement (1)
-	-	1	not provided (1)
-	-	1	Striatal degeneration, autosomal dominant 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.8
DANN	Benign	0.61
PhyloP100		-0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs220740; hg19: chr6-165832227; COSMIC: COSV63097189;