Genetic Variant SORCS2:p.Thr146Met (chr4-7193083-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020777.3(SORCS2):c.437C>T(p.Thr146Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. T146R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SORCS2
NM_020777.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.62

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36928353).

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.437C>T	p.Thr146Met	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.437C>T	p.Thr146Met	missense	Exon 1 of 27	ENSP00000422185.2	Q96PQ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1408872

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700618

African (AFR)

AF:

0.00

AC:

AN:

29816

American (AMR)

AF:

0.00

AC:

AN:

41284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24948

East Asian (EAS)

AF:

0.00

AC:

AN:

34506

South Asian (SAS)

AF:

0.00

AC:

AN:

82730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095076

Other (OTH)

AF:

0.00

AC:

AN:

58550

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0085

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.37

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

2.6

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.1

REVEL

Benign

0.14

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.26

MutPred

0.67

Gain of ubiquitination at K142 (P = 0.0898)

MVP

0.68

MPC

0.42

ClinPred

0.78

GERP RS

3.9

Varity_R

0.089

gMVP

0.21

Mutation Taster

=85/15

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over