rs1048621

Positions:

• chr20-1312402-G-A
• chr20-1312402-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_080489.5(SDCBP2):​c.667C>T​(p.Arg223Cys) variant causes a missense change. The variant allele was found at a frequency of 0.252 in 1,612,836 control chromosomes in the GnomAD database, including 54,492 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.22 (3935 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50557 hom.)
• Consequence: SDCBP2 NM_080489.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.05

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002702564).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDCBP2	NM_080489.5	c.667C>T	p.Arg223Cys	missense_variant	7/9	ENST00000360779.4	NP_536737.3
SDCBP2	NM_001199784.2	c.667C>T	p.Arg223Cys	missense_variant	7/9		NP_001186713.1
SDCBP2	NM_015685.6	c.412C>T	p.Arg138Cys	missense_variant	3/5		NP_056500.2
FKBP1A-SDCBP2	NR_037661.1	n.945C>T		non_coding_transcript_exon_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDCBP2	ENST00000360779.4	c.667C>T	p.Arg223Cys	missense_variant	7/9	1	NM_080489.5	ENSP00000354013.3
SDCBP2	ENST00000339987.7	c.667C>T	p.Arg223Cys	missense_variant	7/9	1		ENSP00000342935.3
SDCBP2	ENST00000381808.7	c.412C>T	p.Arg138Cys	missense_variant	3/5	1		ENSP00000371229.3
SDCBP2	ENST00000381812.5	c.667C>T	p.Arg223Cys	missense_variant	7/9	5		ENSP00000371233.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33339 AN: 152012 Hom.: 3937 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0174

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.226

GnomAD3 exomes AF: 0.204 AC: 50596 AN: 248036 Hom.: 5991 AF XY: 0.206 AC XY: 27682 AN XY: 134324

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.0169

Gnomad SAS exome AF: 0.134

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.255 AC: 372562 AN: 1460706 Hom.: 50557 Cov.: 60 AF XY: 0.252 AC XY: 183066 AN XY: 726538

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.0126

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.284

Gnomad4 OTH exome AF: 0.233

GnomAD4 genome AF: 0.219 AC: 33342 AN: 152130 Hom.: 3935 Cov.: 32 AF XY: 0.215 AC XY: 15960 AN XY: 74372

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.210

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.0174

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.223

Alfa AF: 0.257 Hom.: 4563

Bravo AF: 0.218

TwinsUK AF: 0.286 AC: 1060

ALSPAC AF: 0.292 AC: 1124

ESP6500AA AF: 0.167 AC: 737

ESP6500EA AF: 0.270 AC: 2320

ExAC AF: 0.202 AC: 24547

Asia WGS AF: 0.0720 AC: 252 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;D;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	.;D;.;D
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.3	M;.;M;M
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-7.6	D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99	D;.;D;D
Vest4		0.26
MPC		0.79
ClinPred		0.072	T
GERP RS		2.8
Varity_R		0.35
gMVP		0.60

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: rs1048621; hg19: chr20-1293046; COSMIC: COSV60588377; COSMIC: COSV60588377;