chr4-7192702-C-A

Variant names:

• chr4-7192702-C-A
• rs1032192515
• NM_020777.3:c.56C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (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
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027520478).
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3	c.56C>A	p.Ala19Asp	missense_variant	Exon 1 of 27	ENST00000507866.6	NP_065828.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS2	ENST00000507866.6	c.56C>A	p.Ala19Asp	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 8 AF XY: 0.00

Gnomad NFE exome AF: 0.00

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

African (AFR) AF: 0.000251 AC: 4 AN: 15934

American (AMR) AF: 0.00228 AC: 3 AN: 1316

Ashkenazi Jewish (ASJ) AF: 0.000561 AC: 3 AN: 5348

East Asian (EAS) AF: 0.00 AC: 0 AN: 3902

South Asian (SAS) AF: 0.00 AC: 0 AN: 17378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1214

Middle Eastern (MID) AF: 0.00121 AC: 2 AN: 1648

European-Non Finnish (NFE) AF: 0.00461 AC: 3538 AN: 768204

Other (OTH) AF: 0.00306 AC: 85 AN: 27822

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

African (AFR) AF: 0.000757 AC: 31 AN: 40976

American (AMR) AF: 0.000946 AC: 14 AN: 14792

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000118 AC: 1 AN: 8482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00363 AC: 239 AN: 65920

Other (OTH) AF: 0.000978 AC: 2 AN: 2044

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

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.82
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
PromoterAI		-0.016	Neutral
Varity_R		0.056
gMVP		0.30
Mutation Taster		=91/9	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

Other links and lift over

dbSNP: rs1032192515; hg19: chr4-7194429;