rs2230766

Variant names:

• chr21-32639102-G-A
• rs2230766
• NM_203446.3:c.3721C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-32639102-G-A
• chr21-32639102-G-T

Variant summary

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

The NM_203446.3(SYNJ1):​c.3721C>T​(p.Leu1241Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0825 in 1,613,350 control chromosomes in the GnomAD database, including 6,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (476 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5589 hom.)
• Consequence: SYNJ1 NM_203446.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.07
• Publications: 8 publications found

Genes affected

SYNJ1 (HGNC:11503): (synaptojanin 1) This gene encodes a phosphoinositide phosphatase that regulates levels of membrane phosphatidylinositol-4,5-bisphosphate. As such, expression of this enzyme may affect synaptic transmission and membrane trafficking. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

SYNJ1 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 53

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• early-onset Parkinson disease 20

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atypical juvenile parkinsonism

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.145).
• BP6: Variant 21-32639102-G-A is Benign according to our data. Variant chr21-32639102-G-A is described in ClinVar as Benign. ClinVar VariationId is 586761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0948 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203446.3. 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
	SYNJ1	NM_203446.3	MANE Select	c.3721C>T	p.Leu1241Leu	synonymous	Exon 31 of 33	NP_982271.3
	SYNJ1	NM_003895.4		c.3838C>T	p.Leu1280Leu	synonymous	Exon 31 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.3580C>T	p.Leu1194Leu	synonymous	Exon 27 of 28	NP_001153778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	ENST00000674351.1	MANE Select	c.3721C>T	p.Leu1241Leu	synonymous	Exon 31 of 33	ENSP00000501530.1
	SYNJ1	ENST00000433931.7	TSL:1	c.3838C>T	p.Leu1280Leu	synonymous	Exon 31 of 32	ENSP00000409667.2
	SYNJ1	ENST00000630077.3	TSL:1	c.3580C>T	p.Leu1194Leu	synonymous	Exon 27 of 28	ENSP00000487560.1

Frequencies

GnomAD3 genomes AF: 0.0675 AC: 10273 AN: 152136 Hom.: 476 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0861

Gnomad ASJ AF: 0.0685

Gnomad EAS AF: 0.00751

Gnomad SAS AF: 0.0611

Gnomad FIN AF: 0.0858

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0968

Gnomad OTH AF: 0.0890

GnomAD2 exomes AF: 0.0719 AC: 18071 AN: 251194 AF XY: 0.0741

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.0748

Gnomad EAS exome AF: 0.00772

Gnomad FIN exome AF: 0.0889

Gnomad NFE exome AF: 0.0968

Gnomad OTH exome AF: 0.0793

GnomAD4 exome AF: 0.0841 AC: 122824 AN: 1461096 Hom.: 5589 Cov.: 31 AF XY: 0.0848 AC XY: 61627 AN XY: 726848

African (AFR) AF: 0.0131 AC: 439 AN: 33464

American (AMR) AF: 0.0483 AC: 2159 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0764 AC: 1995 AN: 26118

East Asian (EAS) AF: 0.00685 AC: 272 AN: 39694

South Asian (SAS) AF: 0.0665 AC: 5733 AN: 86184

European-Finnish (FIN) AF: 0.0915 AC: 4886 AN: 53408

Middle Eastern (MID) AF: 0.0947 AC: 543 AN: 5736

European-Non Finnish (NFE) AF: 0.0917 AC: 101912 AN: 1111450

Other (OTH) AF: 0.0809 AC: 4885 AN: 60360

GnomAD4 genome AF: 0.0675 AC: 10272 AN: 152254 Hom.: 476 Cov.: 32 AF XY: 0.0666 AC XY: 4958 AN XY: 74436

African (AFR) AF: 0.0147 AC: 613 AN: 41562

American (AMR) AF: 0.0860 AC: 1315 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0685 AC: 238 AN: 3472

East Asian (EAS) AF: 0.00753 AC: 39 AN: 5182

South Asian (SAS) AF: 0.0614 AC: 296 AN: 4824

European-Finnish (FIN) AF: 0.0858 AC: 910 AN: 10604

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0968 AC: 6581 AN: 67996

Other (OTH) AF: 0.0881 AC: 186 AN: 2112

Alfa AF: 0.0659 Hom.: 352

Bravo AF: 0.0623

EpiCase AF: 0.0965

EpiControl AF: 0.0933

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.5
DANN	Benign	0.66
PhyloP100		2.1
Mutation Taster		=99/1	polymorphism (auto)

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: rs2230766; hg19: chr21-34011412; COSMIC: COSV59157743;