chr20-1312653-G-A

Variant names:

• chr20-1312653-G-A
• rs1335095958
• NM_080489.5:c.494C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080489.5(SDCBP2):​c.494C>T​(p.Ser165Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,864 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S165A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (1 hom.)
• Consequence: SDCBP2 NM_080489.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

Genes affected

SDCBP2 (HGNC:15756): (syndecan binding protein 2) The protein encoded by this gene contains two class II PDZ domains. PDZ domains facilitate protein-protein interactions by binding to the cytoplasmic C-terminus of transmembrane proteins, and PDZ-containing proteins mediate cell signaling and the organization of protein complexes. The encoded protein binds to phosphatidylinositol 4, 5-bisphosphate (PIP2) and plays a role in nuclear PIP2 organization and cell division. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Read-through transcription also exists between this gene and the upstream FKBP1A (FK506 binding protein 1A, 12kDa) gene, as represented in GeneID:100528031. [provided by RefSeq, Sep 2011]

FKBP1A-SDCBP2 (HGNC:41997): (FKBP1A-SDCBP2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring FK506 binding protein 1A, 12kDa and syndecan binding protein (syntenin) 2 genes on chromosome 20. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13362831).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDCBP2	NM_080489.5	c.494C>T	p.Ser165Leu	missense_variant	Exon 6 of 9	ENST00000360779.4	NP_536737.3
SDCBP2	NM_001199784.2	c.494C>T	p.Ser165Leu	missense_variant	Exon 6 of 9		NP_001186713.1
SDCBP2	NM_015685.6	c.239C>T	p.Ser80Leu	missense_variant	Exon 2 of 5		NP_056500.2
FKBP1A-SDCBP2	NR_037661.1	n.772C>T		non_coding_transcript_exon_variant	Exon 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDCBP2	ENST00000360779.4	c.494C>T	p.Ser165Leu	missense_variant	Exon 6 of 9	1	NM_080489.5	ENSP00000354013.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461864 Hom.: 1 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.494C>T (p.S165L) alteration is located in exon 6 (coding exon 5) of the SDCBP2 gene. This alteration results from a C to T substitution at nucleotide position 494, causing the serine (S) at amino acid position 165 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	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;.;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.92	.;D;.;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.36	N;.;N;N
PhyloP100		3.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.58	N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.084	B;.;B;B
Vest4		0.20
MutPred		0.50		Loss of disorder (P = 0.0172);.;Loss of disorder (P = 0.0172);Loss of disorder (P = 0.0172);
MVP		0.33
MPC		0.14
ClinPred		0.39	T
GERP RS		4.5
Varity_R		0.13
gMVP		0.25
Mutation Taster		=81/19	polymorphism

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: rs1335095958; hg19: chr20-1293297; COSMIC: COSV60588630; COSMIC: COSV60588630;