4-7192725-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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. 14/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0520

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075332522).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome 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 gnomad4_exome. There are 134 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORCS2	NM_020777.3	c.79C>T	p.Pro27Ser	missense_variant	1/27	ENST00000507866.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORCS2	ENST00000507866.6	c.79C>T	p.Pro27Ser	missense_variant	1/27	1	NM_020777.3	P1

Frequencies

GnomAD3 genomes AF: 0.00393 AC: 575 AN: 146384 Hom.: 2 Cov.: 32

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

GnomAD4 exome AF: 0.000389 AC: 328 AN: 844266 Hom.: 5 Cov.: 29 AF XY: 0.000343 AC XY: 134 AN XY: 391178

Gnomad4 AFR exome AF: 0.0194

Gnomad4 AMR exome AF: 0.000732

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000390

Gnomad4 OTH exome AF: 0.000502

GnomAD4 genome AF: 0.00393 AC: 575 AN: 146488 Hom.: 2 Cov.: 32 AF XY: 0.00377 AC XY: 269 AN XY: 71326

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.00102

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00343

Alfa AF: 0.000571 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

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
MutationTaster	Benign	1.0	N
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
Varity_R		0.022
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs970393286; hg19: chr4-7194452;