4-7192702-C-A

Variant summary

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

The NM_020777.3(SORCS2):c.56C>A(p.Ala19Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 989,472 control chromosomes in the GnomAD database, including 10 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 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (10 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.819

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=0.027520478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORCS2	NM_020777.3	c.56C>A	p.Ala19Asp	missense_variant	1/27	ENST00000507866.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORCS2	ENST00000507866.6	c.56C>A	p.Ala19Asp	missense_variant	1/27	1	NM_020777.3	P1

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 292 AN: 146604 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000759

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000948

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000118

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.000989

GnomAD4 exome AF: 0.00431 AC: 3635 AN: 842766 Hom.: 10 Cov.: 29 AF XY: 0.00429 AC XY: 1675 AN XY: 390228

Gnomad4 AFR exome AF: 0.000251

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.000561

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00461

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.00199 AC: 292 AN: 146706 Hom.: 0 Cov.: 32 AF XY: 0.00178 AC XY: 127 AN XY: 71424

Gnomad4 AFR AF: 0.000757

Gnomad4 AMR AF: 0.000946

Gnomad4 ASJ AF: 0.00118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000118

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.000978

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.00214

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

Sep 15, 2021

The c.56C>A (p.A19D) 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 56, causing the alanine (A) at amino acid position 19 to be replaced by an aspartic acid (D). 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	0.18
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	14
Dann	Benign	0.48
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.0060
Sift	Benign	0.55	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.52
MPC		2.5
ClinPred		0.026	T
GERP RS		1.2
Varity_R		0.056
gMVP		0.30

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: rs1032192515; hg19: chr4-7194429;