Genetic Variant SORCS2:p.His61Tyr (chr4-7192827-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020777.3(SORCS2):c.181C>T(p.His61Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 888,370 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: not found (cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SORCS2
NM_020777.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.10

Publications

0 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: 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=0.060007304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3 link	c.181C>T	p.His61Tyr	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.181C>T	p.His61Tyr	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2		Q96PQ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000180

AC:

AN:

888370

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

414994

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16916

American (AMR)

AF:

0.00

AC:

AN:

2802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6608

East Asian (EAS)

AF:

0.000154

AC:

AN:

6474

South Asian (SAS)

AF:

0.00

AC:

AN:

17826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1870

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

798702

Other (OTH)

AF:

0.00

AC:

AN:

30540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.181C>T (p.H61Y) alteration is located in exon 1 (coding exon 1) of the SORCS2 gene. This alteration results from a C to T substitution at nucleotide position 181, causing the histidine (H) at amino acid position 61 to be replaced by a tyrosine (Y). 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

0.081

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0047

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.33

M_CAP

Benign

0.017

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

-1.1

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.62

REVEL

Benign

0.0040

Sift

Benign

0.24

Sift4G

Benign

0.26

Polyphen

0.023

Vest4

0.14

MutPred

0.24

Gain of phosphorylation at H61 (P = 0.0123);

MVP

0.57

MPC

2.1

ClinPred

0.060

GERP RS

-2.7

PromoterAI

0.038

Neutral

(source)

Varity_R

0.039

gMVP

0.19

Mutation Taster

=97/3

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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chr4-7192827-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over