NM_020777.3:c.217G>A

Variant names:

• chr4-7192863-G-A
• rs1039738941
• NM_020777.3:c.217G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020777.3(SORCS2):​c.217G>A​(p.Ala73Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000959 in 1,064,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.207
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059890658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3	c.217G>A	p.Ala73Thr	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.217G>A	p.Ala73Thr	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2

Frequencies

GnomAD3 genomes AF: 0.000115 AC: 17 AN: 147862 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000739

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000905

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 22 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000928 AC: 85 AN: 916170 Hom.: 0 Cov.: 30 AF XY: 0.0000954 AC XY: 41 AN XY: 429616

African (AFR) AF: 0.00 AC: 0 AN: 17674

American (AMR) AF: 0.000285 AC: 1 AN: 3512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7546

East Asian (EAS) AF: 0.00 AC: 0 AN: 8840

South Asian (SAS) AF: 0.0000549 AC: 1 AN: 18202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2030

European-Non Finnish (NFE) AF: 0.0000967 AC: 79 AN: 816752

Other (OTH) AF: 0.000124 AC: 4 AN: 32210

GnomAD4 genome AF: 0.000115 AC: 17 AN: 147968 Hom.: 0 Cov.: 32 AF XY: 0.0000832 AC XY: 6 AN XY: 72084

African (AFR) AF: 0.00 AC: 0 AN: 41138

American (AMR) AF: 0.000738 AC: 11 AN: 14906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9042

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

European-Non Finnish (NFE) AF: 0.0000905 AC: 6 AN: 66290

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000162

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217G>A (p.A73T) alteration is located in exon 1 (coding exon 1) of the SORCS2 gene. This alteration results from a G to A substitution at nucleotide position 217, causing the alanine (A) at amino acid position 73 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.21
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.019
Sift	Benign	0.28	T
Sift4G	Benign	0.25	T
Polyphen		0.38	B
Vest4		0.053
MutPred		0.21		Gain of phosphorylation at A73 (P = 0.0031);
MVP		0.32
MPC		1.8
ClinPred		0.081	T
GERP RS		0.75
PromoterAI		0.0062	Neutral
Varity_R		0.032
gMVP		0.16
Mutation Taster		=100/0	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: rs1039738941; hg19: chr4-7194590;