4-7192683-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020777.3(SORCS2):c.37C>T(p.Pro13Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 988,626 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.92

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048635602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORCS2	NM_020777.3	c.37C>T	p.Pro13Ser	missense_variant	1/27	ENST00000507866.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORCS2	ENST00000507866.6	c.37C>T	p.Pro13Ser	missense_variant	1/27	1	NM_020777.3	P1

Frequencies

GnomAD3 genomes AF: 0.000954 AC: 140 AN: 146676 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000351

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.000494

GnomAD4 exome AF: 0.00169 AC: 1424 AN: 841844 Hom.: 3 Cov.: 30 AF XY: 0.00170 AC XY: 664 AN XY: 389710

Gnomad4 AFR exome AF: 0.000251

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000576

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00180

Gnomad4 OTH exome AF: 0.00122

GnomAD4 genome AF: 0.000954 AC: 140 AN: 146782 Hom.: 0 Cov.: 32 AF XY: 0.000686 AC XY: 49 AN XY: 71476

Gnomad4 AFR AF: 0.000464

Gnomad4 AMR AF: 0.000203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000351

Gnomad4 NFE AF: 0.00173

Gnomad4 OTH AF: 0.000488

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.000869

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

Oct 06, 2021

The c.37C>T (p.P13S) 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 37, causing the proline (P) at amino acid position 13 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	0.085
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.018
Sift	Benign	0.040	D
Sift4G	Benign	0.067	T
Polyphen		0.0020	B
Vest4		0.076
MVP		0.37
MPC		1.8
ClinPred		0.060	T
GERP RS		0.10
Varity_R		0.032
gMVP		0.20

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: rs1047727737; hg19: chr4-7194410;