NM_020777.3:c.53G>A

Variant names:

• chr4-7192699-G-A
• rs1329626385
• NM_020777.3:c.53G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020777.3(SORCS2):​c.53G>A​(p.Arg18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 988,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R18L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0350
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054153234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3	c.53G>A	p.Arg18Gln	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.53G>A	p.Arg18Gln	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 146406 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000304

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000190 AC: 16 AN: 842550 Hom.: 0 Cov.: 29 AF XY: 0.00000769 AC XY: 3 AN XY: 390108

African (AFR) AF: 0.00 AC: 0 AN: 15936

American (AMR) AF: 0.00 AC: 0 AN: 1310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5342

East Asian (EAS) AF: 0.000257 AC: 1 AN: 3896

South Asian (SAS) AF: 0.00 AC: 0 AN: 17370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1644

European-Non Finnish (NFE) AF: 0.0000195 AC: 15 AN: 768062

Other (OTH) AF: 0.00 AC: 0 AN: 27800

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 146406 Hom.: 0 Cov.: 32 AF XY: 0.0000281 AC XY: 2 AN XY: 71220

African (AFR) AF: 0.00 AC: 0 AN: 40808

American (AMR) AF: 0.00 AC: 0 AN: 14768

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5066

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000304 AC: 2 AN: 65860

Other (OTH) AF: 0.00 AC: 0 AN: 2020

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.53G>A (p.R18Q) alteration is located in exon 1 (coding exon 1) of the SORCS2 gene. This alteration results from a G to A substitution at nucleotide position 53, causing the arginine (R) at amino acid position 18 to be replaced by a glutamine (Q). 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	0.24
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.035
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.0080
Sift	Benign	0.22	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.081
MutPred		0.36		Loss of methylation at R18 (P = 0.0097);
MVP		0.40
MPC		2.1
ClinPred		0.041	T
GERP RS		0.67
PromoterAI		-0.0086	Neutral
Varity_R		0.026
gMVP		0.20
Mutation Taster		=96/4	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: rs1329626385; hg19: chr4-7194426;