4-7192692-A-C

Variant names:

• chr4-7192692-A-C
• rs1249328324
• NM_020777.3:c.46A>C

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.46A>C​(p.Thr16Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000405 in 987,614 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. T16S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.19
• 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=0.05384767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3	c.46A>C	p.Thr16Pro	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.46A>C	p.Thr16Pro	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2

Frequencies

GnomAD3 genomes AF: 0.00000689 AC: 1 AN: 145158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000249

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000356 AC: 3 AN: 842456 Hom.: 0 Cov.: 29 AF XY: 0.00000769 AC XY: 3 AN XY: 390026

African (AFR) AF: 0.000188 AC: 3 AN: 15938

American (AMR) AF: 0.00 AC: 0 AN: 1322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5344

East Asian (EAS) AF: 0.00 AC: 0 AN: 3898

South Asian (SAS) AF: 0.00 AC: 0 AN: 17368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1174

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 767972

Other (OTH) AF: 0.00 AC: 0 AN: 27794

GnomAD4 genome AF: 0.00000689 AC: 1 AN: 145158 Hom.: 0 Cov.: 32 AF XY: 0.0000142 AC XY: 1 AN XY: 70604

African (AFR) AF: 0.0000249 AC: 1 AN: 40220

American (AMR) AF: 0.00 AC: 0 AN: 14702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 4954

South Asian (SAS) AF: 0.00 AC: 0 AN: 4748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65540

Other (OTH) AF: 0.00 AC: 0 AN: 2012

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46A>C (p.T16P) alteration is located in exon 1 (coding exon 1) of the SORCS2 gene. This alteration results from a A to C substitution at nucleotide position 46, causing the threonine (T) at amino acid position 16 to be replaced by a proline (P). 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	0.049
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	10
DANN	Benign	0.37
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.068
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.080
MutPred		0.20		Loss of phosphorylation at T16 (P = 0.0041);
MVP		0.36
MPC		2.2
ClinPred		0.050	T
GERP RS		-4.6
PromoterAI		-0.0010	Neutral
Varity_R		0.062
gMVP		0.13
Mutation Taster		=93/7	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: rs1249328324; hg19: chr4-7194419;