4-7192681-G-T

Variant names:

• chr4-7192681-G-T
• rs941954703
• NM_020777.3:c.35G>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.35G>T​(p.Gly12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000202 in 988,396 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 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71
• Publications: 1 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=0.07840535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3	c.35G>T	p.Gly12Val	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.35G>T	p.Gly12Val	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2

Frequencies

GnomAD3 genomes AF: 0.00000682 AC: 1 AN: 146672 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000245

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: 0.00000119 AC: 1 AN: 841724 Hom.: 0 Cov.: 29 AF XY: 0.00000257 AC XY: 1 AN XY: 389638

African (AFR) AF: 0.0000628 AC: 1 AN: 15924

American (AMR) AF: 0.00 AC: 0 AN: 1290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5326

East Asian (EAS) AF: 0.00 AC: 0 AN: 3862

South Asian (SAS) AF: 0.00 AC: 0 AN: 17358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1640

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 767464

Other (OTH) AF: 0.00 AC: 0 AN: 27760

GnomAD4 genome AF: 0.00000682 AC: 1 AN: 146672 Hom.: 0 Cov.: 32 AF XY: 0.0000140 AC XY: 1 AN XY: 71358

African (AFR) AF: 0.0000245 AC: 1 AN: 40860

American (AMR) AF: 0.00 AC: 0 AN: 14778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8566

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65936

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35G>T (p.G12V) alteration is located in exon 1 (coding exon 1) of the SORCS2 gene. This alteration results from a G to T substitution at nucleotide position 35, causing the glycine (G) at amino acid position 12 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	0.098
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.019
Sift	Benign	0.32	T
Sift4G	Benign	0.66	T
Polyphen		0.032	B
Vest4		0.11
MutPred		0.27		Loss of catalytic residue at G12 (P = 0.0269);
MVP		0.63
MPC		2.2
ClinPred		0.080	T
GERP RS		1.5
PromoterAI		-0.11	Neutral
Varity_R		0.065
gMVP		0.12
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: rs941954703; hg19: chr4-7194408;