Genetic Variant SORCS1:c.3371+210A>G (chr10-106579159-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001387556.1(SORCS1):c.3464A>G(p.Asn1155Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,614,072 control chromosomes in the GnomAD database, including 2,201 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.039 ( 315 hom., cov: 32)

Exomes 𝑓: 0.019 ( 1886 hom. )

Consequence

SORCS1
NM_001387556.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0930

Publications

8 publications found

Variant links:

Genes affected

SORCS1 (HGNC:16697): (sortilin related VPS10 domain containing receptor 1) 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. Two of the five family members (sortilin and sortilin-related receptor) are synthesized as preproproteins; it is not yet known if this encoded protein is also a preproprotein. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

SORCS1 Gene-Disease associations (from GenCC):

schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

SORCS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029719472).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387556.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SORCS1	NM_052918.5	MANE Select	c.3371+210A>G		intron	N/A	NP_443150.3
SORCS1	NM_001387556.1		c.3464A>G	p.Asn1155Ser	missense	Exon 26 of 27	NP_001374485.1
SORCS1	NM_001013031.3		c.3464A>G	p.Asn1155Ser	missense	Exon 26 of 27	NP_001013049.1	Q8WY21-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SORCS1	ENST00000263054.11	TSL:1 MANE Select	c.3371+210A>G		intron	N/A	ENSP00000263054.5	Q8WY21-1
SORCS1	ENST00000369698.6	TSL:5	c.2195A>G	p.Asn732Ser	missense	Exon 18 of 19	ENSP00000358712.2	X6R7D6
SORCS1	ENST00000452214.5	TSL:3	c.506A>G	p.Asn169Ser	missense	Exon 5 of 6	ENSP00000407769.1	H7C2U3

Frequencies

GnomAD3 genomes

AF:

0.0390

AC:

5932

AN:

152116

Hom.:

315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0513

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0955

Gnomad ASJ

AF:

0.0306

Gnomad EAS

AF:

0.248

Gnomad SAS

AF:

0.0717

Gnomad FIN

AF:

0.0362

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00225

Gnomad OTH

AF:

0.0344

GnomAD2 exomes

AF:

0.0513

AC:

12905

AN:

251332

AF XY:

0.0468

show subpopulations

Gnomad AFR exome

AF:

0.0520

Gnomad AMR exome

AF:

0.120

Gnomad ASJ exome

AF:

0.0299

Gnomad EAS exome

AF:

0.257

Gnomad FIN exome

AF:

0.0299

Gnomad NFE exome

AF:

0.00258

Gnomad OTH exome

AF:

0.0325

GnomAD4 exome

AF:

0.0187

AC:

27301

AN:

1461836

Hom.:

1886

Cov.:

AF XY:

0.0191

AC XY:

13917

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.0510

AC:

1708

AN:

33476

American (AMR)

AF:

0.116

AC:

5198

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0303

AC:

792

AN:

26134

East Asian (EAS)

AF:

0.247

AC:

9819

AN:

39700

South Asian (SAS)

AF:

0.0567

AC:

4891

AN:

86258

European-Finnish (FIN)

AF:

0.0283

AC:

1509

AN:

53416

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00138

AC:

1537

AN:

1111974

Other (OTH)

AF:

0.0293

AC:

1768

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1594

3188

4781

6375

7969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

374

748

1122

1496

1870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0390

AC:

5936

AN:

152236

Hom.:

315

Cov.:

AF XY:

0.0436

AC XY:

3249

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0513

AC:

2131

AN:

41556

American (AMR)

AF:

0.0956

AC:

1461

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0306

AC:

106

AN:

3466

East Asian (EAS)

AF:

0.248

AC:

1276

AN:

5152

South Asian (SAS)

AF:

0.0718

AC:

346

AN:

4820

European-Finnish (FIN)

AF:

0.0362

AC:

384

AN:

10620

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00223

AC:

152

AN:

68022

Other (OTH)

AF:

0.0355

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

267

535

802

1070

1337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0166

Hom.:

407

Bravo

AF:

0.0439

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.0572

AC:

252

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.0457

AC:

5555

Asia WGS

AF:

0.135

AC:

467

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00267

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.9

(source)

DANN

Benign

0.67

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.98

PhyloP100

0.093

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.32

REVEL

Benign

0.062

Sift

Benign

0.28

Sift4G

Benign

0.43

Vest4

0.027

MPC

0.20

ClinPred

0.0034

GERP RS

-6.6

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over