NM_020777.3:c.79C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_020777.3(SORCS2):​c.79C>T​(p.Pro27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000911 in 990,754 control chromosomes in the GnomAD database, including 7 homozygotes. 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: 𝑓 0.0039 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00039 ( 5 hom. )

Consequence

SORCS2
NM_020777.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0520

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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0075332522).
BS1
Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000389 (328/844266) while in subpopulation AFR AF = 0.0194 (309/15956). AF 95% confidence interval is 0.0176. There are 5 homozygotes in GnomAdExome4. There are 134 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SORCS2NM_020777.3 linkc.79C>T p.Pro27Ser 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
SORCS2ENST00000507866.6 linkc.79C>T p.Pro27Ser missense_variant Exon 1 of 27 1 NM_020777.3 ENSP00000422185.2 Q96PQ0

Frequencies

GnomAD3 genomes
AF:
0.00393
AC:
575
AN:
146384
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0135
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00102
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00347
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
14
AF XY:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000389
AC:
328
AN:
844266
Hom.:
5
Cov.:
29
AF XY:
0.000343
AC XY:
134
AN XY:
391178
show subpopulations
African (AFR)
AF:
0.0194
AC:
309
AN:
15956
American (AMR)
AF:
0.000732
AC:
1
AN:
1366
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
5360
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3964
South Asian (SAS)
AF:
0.00
AC:
0
AN:
17400
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
1358
Middle Eastern (MID)
AF:
0.000605
AC:
1
AN:
1652
European-Non Finnish (NFE)
AF:
0.00000390
AC:
3
AN:
769296
Other (OTH)
AF:
0.000502
AC:
14
AN:
27914
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
19
38
56
75
94
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.00393
AC:
575
AN:
146488
Hom.:
2
Cov.:
32
AF XY:
0.00377
AC XY:
269
AN XY:
71326
show subpopulations
African (AFR)
AF:
0.0135
AC:
552
AN:
40926
American (AMR)
AF:
0.00102
AC:
15
AN:
14762
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3386
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5074
South Asian (SAS)
AF:
0.000208
AC:
1
AN:
4812
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
8444
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
286
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
65844
Other (OTH)
AF:
0.00343
AC:
7
AN:
2042
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
30
61
91
122
152
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
10
20
30
40
50
<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:
0.000571
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 07, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.79C>T (p.P27S) 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 79, causing the proline (P) at amino acid position 27 to be replaced by a serine (S). 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
0.077
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
7.0
DANN
Benign
0.85
DEOGEN2
Benign
0.0038
T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.065
N
LIST_S2
Benign
0.34
T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.0075
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.0
N
PhyloP100
0.052
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
0.030
N
REVEL
Benign
0.018
Sift
Benign
0.13
T
Sift4G
Uncertain
0.025
D
Polyphen
0.0
B
Vest4
0.13
MutPred
0.35
Gain of phosphorylation at P27 (P = 0.0011);
MVP
0.14
MPC
2.7
ClinPred
0.041
T
GERP RS
0.63
PromoterAI
-0.040
Neutral
Varity_R
0.022
gMVP
0.28
Mutation Taster
=89/11
polymorphism

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

Other links and lift over

dbSNP: rs970393286; hg19: chr4-7194452; API