rs1462893399

Variant names:

• chr4-7193080-C-T
• rs1462893399
• NM_020777.3:c.434C>T

Variant summary

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

The NM_020777.3(SORCS2):​c.434C>T​(p.Ala145Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,409,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020777.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORCS2	NM_020777.3	MANE Select	c.434C>T	p.Ala145Val	missense	Exon 1 of 27	NP_065828.2	Q96PQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORCS2	ENST00000507866.6	TSL:1 MANE Select	c.434C>T	p.Ala145Val	missense	Exon 1 of 27	ENSP00000422185.2	Q96PQ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1409036 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 700672

African (AFR) AF: 0.00 AC: 0 AN: 29808

American (AMR) AF: 0.00 AC: 0 AN: 41278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24966

East Asian (EAS) AF: 0.00 AC: 0 AN: 34586

South Asian (SAS) AF: 0.00 AC: 0 AN: 82672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1095210

Other (OTH) AF: 0.00 AC: 0 AN: 58578

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.010	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.30
MutPred		0.44		Gain of sheet (P = 0.0827)
MVP		0.74
MPC		0.32
ClinPred		0.92	D
GERP RS		3.9
Varity_R		0.26
gMVP		0.24
Mutation Taster		=51/49	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: rs1462893399; hg19: chr4-7194807;