10-106688226-G-T

Variant names:

• chr10-106688226-G-T
• rs140516942
• NM_052918.5:c.1526C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052918.5(SORCS1):​c.1526C>A​(p.Thr509Lys) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T509M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SORCS1 NM_052918.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73

Genes affected

SORCS1 (HGNC:16697): (sortilin related VPS10 domain containing receptor 1) This gene encodes one family member of vacuolar protein sorting 10 (VPS10) domain-containing receptor proteins. The VPS10 domain name comes from the yeast carboxypeptidase Y sorting receptor Vps10 protein. Members of this gene family are large with many exons but the CDS lengths are usually less than 3700 nt. Very large introns typically separate the exons encoding the VPS10 domain; the remaining exons are separated by much smaller-sized introns. These genes are strongly expressed in the central nervous system. Two of the five family members (sortilin and sortilin-related receptor) are synthesized as preproproteins; it is not yet known if this encoded protein is also a preproprotein. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14973879).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS1	NM_052918.5	c.1526C>A	p.Thr509Lys	missense_variant	Exon 10 of 26	ENST00000263054.11	NP_443150.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS1	ENST00000263054.11	c.1526C>A	p.Thr509Lys	missense_variant	Exon 10 of 26	1	NM_052918.5	ENSP00000263054.5
SORCS1	ENST00000369698.6	c.257C>A	p.Thr86Lys	missense_variant	Exon 2 of 19	5		ENSP00000358712.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1526C>A (p.T509K) alteration is located in exon 10 (coding exon 10) of the SORCS1 gene. This alteration results from a C to A substitution at nucleotide position 1526, causing the threonine (T) at amino acid position 509 to be replaced by a lysine (K). 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	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;.;T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.62	T;T;T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;.;.;.
PhyloP100		2.7
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.6	D;.;.;D;.
REVEL	Benign	0.11
Sift	Benign	0.094	T;.;.;T;.
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.0070	B;.;.;.;.
Vest4		0.26
MutPred		0.44		Gain of ubiquitination at T509 (P = 0.0185);.;.;.;.;
MVP		0.10
MPC		0.30
ClinPred		0.67	D
GERP RS		6.2
Varity_R		0.22
gMVP		0.79
Mutation Taster		=93/7	polymorphism

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

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Other links and lift over

dbSNP: rs140516942; hg19: chr10-108447984;