20-1313450-C-A

Variant names:

• chr20-1313450-C-A
• rs753344660
• NM_080489.5:c.274G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_080489.5(SDCBP2):​c.274G>T​(p.Gly92Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G92R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SDCBP2 NM_080489.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.49
• Publications: 0 publications found

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080489.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDCBP2	NM_080489.5	MANE Select	c.274G>T	p.Gly92Trp	missense	Exon 5 of 9	NP_536737.3
	SDCBP2	NM_001199784.2		c.274G>T	p.Gly92Trp	missense	Exon 5 of 9	NP_001186713.1	Q9H190-1
	SDCBP2	NM_015685.6		c.19G>T	p.Gly7Trp	missense	Exon 1 of 5	NP_056500.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDCBP2	ENST00000360779.4	TSL:1 MANE Select	c.274G>T	p.Gly92Trp	missense	Exon 5 of 9	ENSP00000354013.3	Q9H190-1
	SDCBP2	ENST00000339987.7	TSL:1	c.274G>T	p.Gly92Trp	missense	Exon 5 of 9	ENSP00000342935.3	Q9H190-1
	SDCBP2	ENST00000381808.7	TSL:1	c.19G>T	p.Gly7Trp	missense	Exon 1 of 5	ENSP00000371229.3	Q9H190-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448294 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719724

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33260

American (AMR) AF: 0.00 AC: 0 AN: 43792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25864

East Asian (EAS) AF: 0.00 AC: 0 AN: 39198

South Asian (SAS) AF: 0.00 AC: 0 AN: 84318

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107598

Other (OTH) AF: 0.00 AC: 0 AN: 59862

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.71		Loss of disorder (P = 0.0084)
MVP		0.61
MPC		0.73
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		-0.032	Neutral
Varity_R		0.70
gMVP		0.83
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs753344660; hg19: chr20-1294094; COSMIC: COSV100378175; COSMIC: COSV100378175;