chr10-106618221-T-C

Variant names:

• chr10-106618221-T-C
• NM_052918.5:c.2848A>G

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.2848A>G​(p.Met950Val) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SORCS1 NM_052918.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89

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=0.15865123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS1	NM_052918.5	c.2848A>G	p.Met950Val	missense_variant	Exon 21 of 26	ENST00000263054.11	NP_443150.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS1	ENST00000263054.11	c.2848A>G	p.Met950Val	missense_variant	Exon 21 of 26	1	NM_052918.5	ENSP00000263054.5
SORCS1	ENST00000369698.6	c.1579A>G	p.Met527Val	missense_variant	Exon 13 of 19	5		ENSP00000358712.2
SORCS1	ENST00000478809.2	n.54A>G		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2848A>G (p.M950V) alteration is located in exon 21 (coding exon 21) of the SORCS1 gene. This alteration results from a A to G substitution at nucleotide position 2848, causing the methionine (M) at amino acid position 950 to be replaced by a valine (V). 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	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.086	T;.;T;.;.
Eigen	Benign	-0.024
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L;.;.;.;.
PhyloP100		3.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.74	N;.;.;N;N
REVEL	Benign	0.097
Sift	Benign	0.32	T;.;.;T;T
Sift4G	Benign	0.75	T;T;T;T;T
Polyphen		0.012	B;.;.;.;.
Vest4		0.20
MutPred		0.34		Gain of sheet (P = 0.0827);.;.;.;.;
MVP		0.043
MPC		0.25
ClinPred		0.57	D
GERP RS		5.3
Varity_R		0.16
gMVP		0.33
Mutation Taster		=90/10	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

hg19: chr10-108377979;