3-42590917-C-T

Position:

• chr3-42590917-C-T

Variant summary

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

The NM_001370300.1(SS18L2):​c.20C>T​(p.Pro7Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000135 in 1,262,872 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 4.31

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/exons	MANE	Protein	UniProt
SS18L2	NM_001370300.1	c.20C>T	p.Pro7Leu	missense_variant	1/3	ENST00000011691.6	NP_001357229.1
SS18L2	NM_016305.4	c.20C>T	p.Pro7Leu	missense_variant	2/4		NP_057389.1
SEC22C	NM_001201572.2	c.-28+10043G>A		intron_variant			NP_001188501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SS18L2	ENST00000011691.6	c.20C>T	p.Pro7Leu	missense_variant	1/3	1	NM_001370300.1	ENSP00000011691.4
SS18L2	ENST00000447630.5	c.20C>T	p.Pro7Leu	missense_variant	2/4	2		ENSP00000401115.1
SEC22C	ENST00000417572.5	c.-28+10043G>A		intron_variant		3		ENSP00000407564.1
SEC22C	ENST00000450981.5	c.-179-3355G>A		intron_variant		3		ENSP00000397170.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000135 AC: 17 AN: 1262872 Hom.: 0 Cov.: 34 AF XY: 0.0000192 AC XY: 12 AN XY: 626060

Gnomad4 AFR exome AF: 0.00

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: 0.0000173

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2024

The c.20C>T (p.P7L) alteration is located in exon 1 (coding exon 1) of the SS18L2 gene. This alteration results from a C to T substitution at nucleotide position 20, causing the proline (P) at amino acid position 7 to be replaced by a leucine (L). 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	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	.;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.85	T
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.087	B;B
Vest4		0.69
MutPred		0.49		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.15
MPC		0.46
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.47
gMVP		0.78

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: rs1704802109; hg19: chr3-42632409;