20-1312498-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_080489.5(SDCBP2):c.571C>T(p.Arg191Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000139 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R191Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: SDCBP2 NM_080489.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDCBP2	NM_080489.5	c.571C>T	p.Arg191Trp	missense_variant	7/9	ENST00000360779.4
FKBP1A-SDCBP2	NR_037661.1	n.849C>T		non_coding_transcript_exon_variant	8/10
SDCBP2	NM_001199784.2	c.571C>T	p.Arg191Trp	missense_variant	7/9
SDCBP2	NM_015685.6	c.316C>T	p.Arg106Trp	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDCBP2	ENST00000360779.4	c.571C>T	p.Arg191Trp	missense_variant	7/9	1	NM_080489.5	P1
SDCBP2	ENST00000339987.7	c.571C>T	p.Arg191Trp	missense_variant	7/9	1		P1
SDCBP2	ENST00000381808.7	c.316C>T	p.Arg106Trp	missense_variant	3/5	1
SDCBP2	ENST00000381812.5	c.571C>T	p.Arg191Trp	missense_variant	7/9	5		P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251084 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000137 AC: 200 AN: 1461806 Hom.: 0 Cov.: 63 AF XY: 0.000124 AC XY: 90 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74342

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

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

Jan 09, 2023

The c.571C>T (p.R191W) alteration is located in exon 7 (coding exon 6) of the SDCBP2 gene. This alteration results from a C to T substitution at nucleotide position 571, causing the arginine (R) at amino acid position 191 to be replaced by a tryptophan (W). 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	0.30
BayesDel_addAF	Benign	-0.0027	T
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;.;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.4	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.9	D;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.029	D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.90
MVP		0.37
MPC		0.29
ClinPred		0.99	D
GERP RS		-0.038
Varity_R		0.76
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs781260947; hg19: chr20-1293142;