rs1379531032

Variant names:

• chr4-7192654-A-C
• rs1379531032
• NM_020777.3:c.8A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-7192654-A-C
• chr4-7192654-A-T

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.8A>C​(p.His3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000811 in 986,872 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 0.000034 (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: -0.542
• 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=0.045269042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3	c.8A>C	p.His3Pro	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.8A>C	p.His3Pro	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2

Frequencies

GnomAD3 genomes AF: 0.0000341 AC: 5 AN: 146810 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000676

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: 0.0000454

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 3 AN: 839952 Hom.: 0 Cov.: 29 AF XY: 0.00000257 AC XY: 1 AN XY: 388612

African (AFR) AF: 0.00 AC: 0 AN: 15890

American (AMR) AF: 0.00 AC: 0 AN: 1204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5290

East Asian (EAS) AF: 0.00 AC: 0 AN: 3800

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 896

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

European-Non Finnish (NFE) AF: 0.00000392 AC: 3 AN: 766260

Other (OTH) AF: 0.00 AC: 0 AN: 27644

GnomAD4 genome AF: 0.0000340 AC: 5 AN: 146920 Hom.: 0 Cov.: 32 AF XY: 0.0000419 AC XY: 3 AN XY: 71592

African (AFR) AF: 0.0000245 AC: 1 AN: 40836

American (AMR) AF: 0.0000675 AC: 1 AN: 14822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5040

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000454 AC: 3 AN: 66008

Other (OTH) AF: 0.00 AC: 0 AN: 2042

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8A>C (p.H3P) 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 8, causing the histidine (H) at amino acid position 3 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	0.040
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.76
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.54
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.044
Sift	Benign	0.18	T
Sift4G	Uncertain	0.034	D
Polyphen		0.0	B
Vest4		0.076
MutPred		0.23		Gain of glycosylation at H3 (P = 0.0362);
MVP		0.26
MPC		2.5
ClinPred		0.042	T
GERP RS		-4.7
PromoterAI		0.033	Neutral
Varity_R		0.099
gMVP		0.19
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: rs1379531032; hg19: chr4-7194381;