3-42590932-G-C

Variant names:

• chr3-42590932-G-C
• rs1388391857
• NM_001370300.1:c.35G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001370300.1(SS18L2):​c.35G>C​(p.Gly12Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,305,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SS18L2 NM_001370300.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

Genes affected

SS18L2 (HGNC:15593): (SS18 like 2) Synovial sarcomas occur most frequently in the extremities around large joints. More than 90% of cases have a recurrent and specific chromosomal translocation, t(X;18)(p11.2;q11.2), in which the 5-prime end of the SS18 gene (MIM 600192) is fused in-frame to the 3-prime end of the SSX1 (MIM 312820), SSX2 (MIM 300192), or SSX4 (MIM 300326) gene. The SS18L2 gene is homologous to SS18.[supplied by OMIM, Jul 2002]

SEC22C (HGNC:16828): (SEC22 homolog C, vesicle trafficking protein) This gene encodes a member of the SEC22 family of vesicle trafficking proteins. The encoded protein is localized to the endoplasmic reticulum and may play a role in the early stages of ER-Golgi protein trafficking. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SS18L2	NM_001370300.1	c.35G>C	p.Gly12Ala	missense_variant	Exon 1 of 3	ENST00000011691.6	NP_001357229.1
SS18L2	NM_016305.4	c.35G>C	p.Gly12Ala	missense_variant	Exon 2 of 4		NP_057389.1
SEC22C	NM_001201572.2	c.-28+10028C>G		intron_variant	Intron 1 of 6		NP_001188501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SS18L2	ENST00000011691.6	c.35G>C	p.Gly12Ala	missense_variant	Exon 1 of 3	1	NM_001370300.1	ENSP00000011691.4
SS18L2	ENST00000447630.5	c.35G>C	p.Gly12Ala	missense_variant	Exon 2 of 4	2		ENSP00000401115.1
SEC22C	ENST00000417572.5	c.-28+10028C>G		intron_variant	Intron 1 of 6	3		ENSP00000407564.1
SEC22C	ENST00000450981.5	c.-179-3370C>G		intron_variant	Intron 1 of 4	3		ENSP00000397170.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250608 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 17 AN: 1305762 Hom.: 0 Cov.: 34 AF XY: 0.0000123 AC XY: 8 AN XY: 648380

Gnomad4 AFR exome AF: 0.0000344

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000138

Gnomad4 OTH exome AF: 0.0000399

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000517 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35G>C (p.G12A) alteration is located in exon 1 (coding exon 1) of the SS18L2 gene. This alteration results from a G to C substitution at nucleotide position 35, causing the glycine (G) at amino acid position 12 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	-0.27	T
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.35
Sift	Benign	0.050	D;D
Sift4G	Benign	0.20	T;T
Polyphen		1.0	D;D
Vest4		0.52
MutPred		0.69		Loss of loop (P = 0.0603);Loss of loop (P = 0.0603);
MVP		0.35
MPC		1.3
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.47
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs1388391857; hg19: chr3-42632424;