rs1038549894

Variant names:

• chr4-7192660-G-C
• rs1038549894
• NM_020777.3:c.14G>C

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.14G>C​(p.Gly5Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 987,340 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.469
• 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=0.087257445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3	c.14G>C	p.Gly5Ala	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.14G>C	p.Gly5Ala	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2

Frequencies

GnomAD3 genomes AF: 0.0000544 AC: 8 AN: 147114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00177

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.000493

GnomAD4 exome AF: 0.00000476 AC: 4 AN: 840226 Hom.: 0 Cov.: 29 AF XY: 0.00000257 AC XY: 1 AN XY: 388748

African (AFR) AF: 0.00 AC: 0 AN: 15898

American (AMR) AF: 0.00 AC: 0 AN: 1218

Ashkenazi Jewish (ASJ) AF: 0.000755 AC: 4 AN: 5298

East Asian (EAS) AF: 0.00 AC: 0 AN: 3812

South Asian (SAS) AF: 0.00 AC: 0 AN: 17330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1638

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 766444

Other (OTH) AF: 0.00 AC: 0 AN: 27662

GnomAD4 genome AF: 0.0000544 AC: 8 AN: 147114 Hom.: 0 Cov.: 32 AF XY: 0.0000698 AC XY: 5 AN XY: 71604

African (AFR) AF: 0.00 AC: 0 AN: 40912

American (AMR) AF: 0.00 AC: 0 AN: 14806

Ashkenazi Jewish (ASJ) AF: 0.00177 AC: 6 AN: 3394

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8730

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

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66098

Other (OTH) AF: 0.000493 AC: 1 AN: 2028

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14G>C (p.G5A) alteration is located in exon 1 (coding exon 1) of the SORCS2 gene. This alteration results from a G to C substitution at nucleotide position 14, causing the glycine (G) at amino acid position 5 to be replaced by an alanine (A). 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	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.47
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.046
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.88	P
Vest4		0.13
MutPred		0.27		Loss of methylation at R4 (P = 0.0562);
MVP		0.52
MPC		1.9
ClinPred		0.21	T
GERP RS		2.4
PromoterAI		-0.10	Neutral
Varity_R		0.16
gMVP		0.14
Mutation Taster		=81/19	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: rs1038549894; hg19: chr4-7194387;