Genetic Variant SORCS2:p.Ala19Val (chr4-7192702-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020777.3(SORCS2):c.56C>T(p.Ala19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00051 in 989,472 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A19D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 2 hom. )

Consequence

SORCS2
NM_020777.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.819

Publications

1 publications found

Variant links:

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]

SORCS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011658847).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3 link	c.56C>T	p.Ala19Val	missense_variant	Exon 1 of 27	ENST00000507866.6	NP_065828.2	Q96PQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS2	ENST00000507866.6 link	c.56C>T	p.Ala19Val	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2		Q96PQ0

Frequencies

GnomAD3 genomes

AF:

0.00247

AC:

362

AN:

146604

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00854

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000474

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:

0.0000152

Gnomad OTH

AF:

0.00247

GnomAD4 exome

AF:

0.000167

AC:

141

AN:

842766

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

AN XY:

390228

show subpopulations

African (AFR)

AF:

0.00816

AC:

130

AN:

15934

American (AMR)

AF:

0.00

AC:

AN:

1316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5348

East Asian (EAS)

AF:

0.00

AC:

AN:

3902

South Asian (SAS)

AF:

0.00

AC:

AN:

17378

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1648

European-Non Finnish (NFE)

AF:

0.00000260

AC:

AN:

768204

Other (OTH)

AF:

0.000323

AC:

AN:

27822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00248

AC:

364

AN:

146706

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

164

AN XY:

71424

show subpopulations

African (AFR)

AF:

0.00857

AC:

351

AN:

40976

American (AMR)

AF:

0.000473

AC:

AN:

14792

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3390

East Asian (EAS)

AF:

0.00

AC:

AN:

5078

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65920

Other (OTH)

AF:

0.00245

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0041

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.45

M_CAP

Benign

0.046

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

0.82

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.010

REVEL

Benign

0.0060

Sift

Benign

0.085

Sift4G

Benign

0.12

Polyphen

0.0

Vest4

0.070

MutPred

0.17

Gain of MoRF binding (P = 0.1076);

MVP

0.43

MPC

1.8

ClinPred

0.058

GERP RS

1.2

PromoterAI

-0.060

Neutral

(source)

Varity_R

0.026

gMVP

0.21

Mutation Taster

=93/7

polymorphism

(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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4-7192702-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over