10-106652402-G-C

Variant summary

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

The NM_052918.5(SORCS1):c.2455C>G(p.Leu819Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SORCS1 NM_052918.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORCS1	NM_052918.5	c.2455C>G	p.Leu819Val	missense_variant	18/26	ENST00000263054.11
LOC105378473	XR_946300.4	n.247+3257G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORCS1	ENST00000263054.11	c.2455C>G	p.Leu819Val	missense_variant	18/26	1	NM_052918.5	P1
	ENST00000662495.1	n.247+3257G>C		intron_variant, non_coding_transcript_variant
SORCS1	ENST00000369698.6	c.1189C>G	p.Leu397Val	missense_variant	10/19	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461798 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.2455C>G (p.L819V) alteration is located in exon 18 (coding exon 18) of the SORCS1 gene. This alteration results from a C to G substitution at nucleotide position 2455, causing the leucine (L) at amino acid position 819 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	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.90	L;.;.;.;.
MutationTaster	Benign	0.64	N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N;.;.;N;.
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D;.;.;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.39	B;.;.;.;.
Vest4		0.52
MutPred		0.65		Loss of sheet (P = 0.0181);.;.;.;.;
MVP		0.16
MPC		0.34
ClinPred		0.51	D
GERP RS		5.6
Varity_R		0.21
gMVP		0.39

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: rs1233016118; hg19: chr10-108412160;