2-20204213-G-A

Position:

• chr2-20204213-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002997.5(SDC1):​c.227C>T​(p.Thr76Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000975 in 1,599,094 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0052 (9 hom., cov: 30)
  • Exomes 𝑓: 0.00053 (10 hom.)
• Consequence: SDC1 NM_002997.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.177

Genes affected

SDC1 (HGNC:10658): (syndecan 1) The protein encoded by this gene is a transmembrane (type I) heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecans mediate cell binding, cell signaling, and cytoskeletal organization and syndecan receptors are required for internalization of the HIV-1 tat protein. The syndecan-1 protein functions as an integral membrane protein and participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins. Altered syndecan-1 expression has been detected in several different tumor types. While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode the same protein. [provided by RefSeq, Jul 2008]

SDC1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-20204213-G-A is Benign according to our data. Variant chr2-20204213-G-A is described in ClinVar as [Benign]. Clinvar id is 720907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00524 (797/152022) while in subpopulation AFR AF= 0.0179 (742/41508). AF 95% confidence interval is 0.0168. There are 9 homozygotes in gnomad4. There are 367 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 797 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDC1	NM_002997.5	c.227C>T	p.Thr76Met	missense_variant	3/5	ENST00000254351.9	NP_002988.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDC1	ENST00000254351.9	c.227C>T	p.Thr76Met	missense_variant	3/5	1	NM_002997.5	ENSP00000254351.4

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 798 AN: 151904 Hom.: 9 Cov.: 30

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00136 AC: 325 AN: 239354 Hom.: 3 AF XY: 0.000998 AC XY: 130 AN XY: 130268

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000711

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000527 AC: 762 AN: 1447072 Hom.: 10 Cov.: 38 AF XY: 0.000471 AC XY: 339 AN XY: 720306

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000846

GnomAD4 genome AF: 0.00524 AC: 797 AN: 152022 Hom.: 9 Cov.: 30 AF XY: 0.00494 AC XY: 367 AN XY: 74316

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.000619 Hom.: 0

Bravo AF: 0.00591

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00172 AC: 209

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.79
DEOGEN2	Uncertain	0.59	D;D;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.61	.;T;T;T
MetaRNN	Benign	0.0042	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M;M;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Benign	0.084
Sift	Benign	0.087	T;T;T;T
Sift4G	Uncertain	0.017	D;D;D;.
Polyphen		0.0090	B;B;B;.
Vest4		0.14
MVP		0.072
MPC		0.39
ClinPred		0.029	T
GERP RS		-0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2230922; hg19: chr2-20403974; COSMIC: COSV99587375;