NM_020777.3:c.44C>T

Variant names:

• chr4-7192690-C-T
• rs891166809
• NM_020777.3:c.44C>T

Variant summary

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

The NM_020777.3(SORCS2):​c.44C>T​(p.Pro15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000758 in 989,120 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (1 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.560
• Publications: 0 publications found

Genes affected

SORCS2 (HGNC:16698): (sortilin related VPS10 domain containing receptor 2) 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. [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=0.08584142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3	c.44C>T	p.Pro15Leu	missense_variant	Exon 1 of 27	ENST00000507866.6	NP_065828.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS2	ENST00000507866.6	c.44C>T	p.Pro15Leu	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2

Frequencies

GnomAD3 genomes AF: 0.0000682 AC: 10 AN: 146698 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000106

Gnomad OTH AF: 0.000495

GnomAD4 exome AF: 0.0000772 AC: 65 AN: 842422 Hom.: 1 Cov.: 29 AF XY: 0.0000692 AC XY: 27 AN XY: 390002

African (AFR) AF: 0.00 AC: 0 AN: 15938

American (AMR) AF: 0.00 AC: 0 AN: 1320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5336

East Asian (EAS) AF: 0.00 AC: 0 AN: 3892

South Asian (SAS) AF: 0.00 AC: 0 AN: 17362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1646

European-Non Finnish (NFE) AF: 0.0000651 AC: 50 AN: 767958

Other (OTH) AF: 0.000540 AC: 15 AN: 27788

GnomAD4 genome AF: 0.0000682 AC: 10 AN: 146698 Hom.: 0 Cov.: 32 AF XY: 0.0000560 AC XY: 4 AN XY: 71370

African (AFR) AF: 0.0000489 AC: 2 AN: 40896

American (AMR) AF: 0.00 AC: 0 AN: 14780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000106 AC: 7 AN: 65924

Other (OTH) AF: 0.000495 AC: 1 AN: 2022

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.44C>T (p.P15L) alteration is located in exon 1 (coding exon 1) of the SORCS2 gene. This alteration results from a C to T substitution at nucleotide position 44, causing the proline (P) at amino acid position 15 to be replaced by a leucine (L). 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	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.56
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.0070
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.088
MutPred		0.26		Loss of glycosylation at P15 (P = 0.0266);
MVP		0.66
MPC		1.9
ClinPred		0.049	T
GERP RS		1.2
PromoterAI		-0.0060	Neutral
Varity_R		0.033
gMVP		0.20
Mutation Taster		=91/9	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

Other links and lift over

dbSNP: rs891166809; hg19: chr4-7194417;