chr4-7192683-C-T

Variant names:

• chr4-7192683-C-T
• rs1047727737
• NM_020777.3:c.37C>T

Variant summary

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

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. 13/22 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
• Publications: 0 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=0.048635602).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3	c.37C>T	p.Pro13Ser	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.37C>T	p.Pro13Ser	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2

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

African (AFR) AF: 0.000251 AC: 4 AN: 15922

American (AMR) AF: 0.00 AC: 0 AN: 1286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5322

East Asian (EAS) AF: 0.00 AC: 0 AN: 3856

South Asian (SAS) AF: 0.0000576 AC: 1 AN: 17358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1642

European-Non Finnish (NFE) AF: 0.00180 AC: 1385 AN: 767564

Other (OTH) AF: 0.00122 AC: 34 AN: 27766

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

African (AFR) AF: 0.000464 AC: 19 AN: 40982

American (AMR) AF: 0.000203 AC: 3 AN: 14808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 5066

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

European-Finnish (FIN) AF: 0.000351 AC: 3 AN: 8544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00173 AC: 114 AN: 65928

Other (OTH) AF: 0.000488 AC: 1 AN: 2048

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

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.9
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
PromoterAI		-0.10	Neutral
Varity_R		0.032
gMVP		0.20
Mutation Taster		=88/12	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: rs1047727737; hg19: chr4-7194410;