Genetic Variant NM_020777.3:c.127C>A (chr4-7192773-C-A) – 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.127C>A(p.Leu43Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000116 in 860,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 0.0000012 ( 0 hom. )

Consequence

SORCS2
NM_020777.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.04

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: 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=0.27731687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3 link	c.127C>A	p.Leu43Met	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.127C>A	p.Leu43Met	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2		Q96PQ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000116

AC:

AN:

860154

Hom.:

Cov.:

AF XY:

0.00000250

AC XY:

AN XY:

400210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16244

American (AMR)

AF:

0.00

AC:

AN:

1966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5712

East Asian (EAS)

AF:

0.00

AC:

AN:

4654

South Asian (SAS)

AF:

0.00

AC:

AN:

17534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1734

European-Non Finnish (NFE)

AF:

0.00000128

AC:

AN:

780178

Other (OTH)

AF:

0.00

AC:

AN:

28870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Mar 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.127C>A (p.L43M) alteration is located in exon 1 (coding exon 1) of the SORCS2 gene. This alteration results from a C to A substitution at nucleotide position 127, causing the leucine (L) at amino acid position 43 to be replaced by a methionine (M). 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

0.25

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0037

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.22

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.28

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

3.0

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.17

REVEL

Benign

0.087

Sift

Benign

0.093

Sift4G

Benign

0.12

Polyphen

0.99

Vest4

0.29

MutPred

0.42

Gain of catalytic residue at L43 (P = 0.0037);

MVP

0.33

MPC

1.8

ClinPred

0.31

GERP RS

2.7

PromoterAI

-0.060

Neutral

(source)

Varity_R

0.058

gMVP

0.13

Mutation Taster

=88/12

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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NM_020777.3:c.127C>A

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