1-202602977-GCCC-GC

Variant names:

• chr1-202602977-GCC-G
• rs55968420
• NM_177402.5:c.465+20_465+21delGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_177402.5(SYT2):​c.465+20_465+21delGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,583,192 control chromosomes in the GnomAD database, including 295,396 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (27352 hom., cov: 0)
  • Exomes 𝑓: 0.61 (268044 hom.)
• Consequence: SYT2 NM_177402.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00
• Publications: 4 publications found

Genes affected

SYT2 (HGNC:11510): (synaptotagmin 2) This gene encodes a synaptic vesicle membrane protein. The encoded protein is thought to function as a calcium sensor in vesicular trafficking and exocytosis. Mutations in this gene are associated with myasthenic syndrome, presynaptic, congenital, with or without motor neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

SYT2 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-202602977-GCC-G is Benign according to our data. Variant chr1-202602977-GCC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177402.5. 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
	SYT2	NM_177402.5	MANE Select	c.465+20_465+21delGG		intron	N/A	NP_796376.2
	SYT2	NM_001136504.1		c.465+20_465+21delGG		intron	N/A	NP_001129976.1	Q8N9I0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT2	ENST00000367268.5	TSL:1 MANE Select	c.465+20_465+21delGG		intron	N/A	ENSP00000356237.4	Q8N9I0
	SYT2	ENST00000930883.1		c.525+20_525+21delGG		intron	N/A	ENSP00000600942.1
	SYT2	ENST00000899895.1		c.474+20_474+21delGG		intron	N/A	ENSP00000569954.1

Frequencies

GnomAD3 genomes AF: 0.610 AC: 90199 AN: 147814 Hom.: 27322 Cov.: 0

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.611

GnomAD2 exomes AF: 0.646 AC: 156800 AN: 242710 AF XY: 0.643

Gnomad AFR exome AF: 0.557

Gnomad AMR exome AF: 0.780

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.695

Gnomad FIN exome AF: 0.623

Gnomad NFE exome AF: 0.615

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.612 AC: 879082 AN: 1435262 Hom.: 268044 AF XY: 0.614 AC XY: 437037 AN XY: 711272

African (AFR) AF: 0.555 AC: 18179 AN: 32754

American (AMR) AF: 0.768 AC: 33223 AN: 43244

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 14036 AN: 25076

East Asian (EAS) AF: 0.711 AC: 27730 AN: 39006

South Asian (SAS) AF: 0.667 AC: 55358 AN: 82950

European-Finnish (FIN) AF: 0.622 AC: 32588 AN: 52396

Middle Eastern (MID) AF: 0.629 AC: 3546 AN: 5638

European-Non Finnish (NFE) AF: 0.601 AC: 658413 AN: 1095168

Other (OTH) AF: 0.610 AC: 36009 AN: 59030

GnomAD4 genome AF: 0.610 AC: 90281 AN: 147930 Hom.: 27352 Cov.: 0 AF XY: 0.614 AC XY: 44228 AN XY: 72052

African (AFR) AF: 0.566 AC: 22554 AN: 39860

American (AMR) AF: 0.707 AC: 10583 AN: 14974

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1812 AN: 3408

East Asian (EAS) AF: 0.699 AC: 3498 AN: 5006

South Asian (SAS) AF: 0.674 AC: 3128 AN: 4642

European-Finnish (FIN) AF: 0.627 AC: 6307 AN: 10052

Middle Eastern (MID) AF: 0.622 AC: 178 AN: 286

European-Non Finnish (NFE) AF: 0.606 AC: 40479 AN: 66776

Other (OTH) AF: 0.613 AC: 1245 AN: 2032

Alfa AF: 0.523 Hom.: 2466

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital myasthenic syndrome 7 (1)
-	-	1	Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	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: rs55968420; hg19: chr1-202572105; COSMIC: COSV66141229; COSMIC: COSV66141229;