2-20204213-G-T

Variant names:

• chr2-20204213-G-T
• rs2230922
• NM_002997.5:c.227C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002997.5(SDC1):​c.227C>A​(p.Thr76Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. T76M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SDC1 NM_002997.5 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12895799).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDC1	NM_002997.5	c.227C>A	p.Thr76Lys	missense_variant	Exon 3 of 5	ENST00000254351.9	NP_002988.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDC1	ENST00000254351.9	c.227C>A	p.Thr76Lys	missense_variant	Exon 3 of 5	1	NM_002997.5	ENSP00000254351.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.0
DANN	Benign	0.58
DEOGEN2	Uncertain	0.67	D;D;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.62	.;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.6	M;M;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Benign	0.072
Sift	Uncertain	0.024	D;D;D;D
Sift4G	Uncertain	0.044	D;D;D;.
Polyphen		0.31	B;B;P;.
Vest4		0.28
MutPred		0.41		Gain of ubiquitination at T76 (P = 0.0037);Gain of ubiquitination at T76 (P = 0.0037);Gain of ubiquitination at T76 (P = 0.0037);.;
MVP		0.23
MPC		0.81
ClinPred		0.44	T
GERP RS		-0.46
Varity_R		0.094
gMVP		0.13

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: rs2230922; hg19: chr2-20403974;