20-1313450-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_080489.5(SDCBP2):c.274G>C(p.Gly92Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,600,518 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: SDCBP2 NM_080489.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDCBP2	NM_080489.5	c.274G>C	p.Gly92Arg	missense_variant	5/9	ENST00000360779.4
FKBP1A-SDCBP2	NR_037661.1	n.552G>C		non_coding_transcript_exon_variant	6/10
SDCBP2	NM_001199784.2	c.274G>C	p.Gly92Arg	missense_variant	5/9
SDCBP2	NM_015685.6	c.19G>C	p.Gly7Arg	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDCBP2	ENST00000360779.4	c.274G>C	p.Gly92Arg	missense_variant	5/9	1	NM_080489.5	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000579 AC: 13 AN: 224350 Hom.: 0 AF XY: 0.0000654 AC XY: 8 AN XY: 122268

Gnomad AFR exome AF: 0.0000732

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000355

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000992

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.000135 AC: 196 AN: 1448296 Hom.: 0 Cov.: 31 AF XY: 0.000138 AC XY: 99 AN XY: 719726

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.0000501

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74368

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

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: 0.00

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000331 AC: 4

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

Dec 13, 2023

The c.274G>C (p.G92R) alteration is located in exon 5 (coding exon 4) of the SDCBP2 gene. This alteration results from a G to C substitution at nucleotide position 274, causing the glycine (G) at amino acid position 92 to be replaced by an arginine (R). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.62	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.2	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.88
MutPred		0.72		Gain of MoRF binding (P = 0.0073);.;Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);
MVP		0.66
MPC		0.70
ClinPred		0.86	D
GERP RS		4.2
Varity_R		0.64
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs753344660; hg19: chr20-1294094;