4-7192716-G-A

Variant names:

• chr4-7192716-G-A
• rs956704380
• NM_020777.3:c.70G>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.70G>A​(p.Ala24Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 989,788 control chromosomes in the GnomAD database, including 2 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 0.00089 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.898
• 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=0.033940375).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020777.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORCS2	NM_020777.3	MANE Select	c.70G>A	p.Ala24Thr	missense	Exon 1 of 27	NP_065828.2	Q96PQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORCS2	ENST00000507866.6	TSL:1 MANE Select	c.70G>A	p.Ala24Thr	missense	Exon 1 of 27	ENSP00000422185.2	Q96PQ0

Frequencies

GnomAD3 genomes AF: 0.000895 AC: 131 AN: 146450 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000271

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: 0.00

Gnomad OTH AF: 0.000496

GnomAD4 exome AF: 0.0000676 AC: 57 AN: 843234 Hom.: 0 Cov.: 29 AF XY: 0.0000538 AC XY: 21 AN XY: 390570

African (AFR) AF: 0.00351 AC: 56 AN: 15936

American (AMR) AF: 0.00 AC: 0 AN: 1330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5350

East Asian (EAS) AF: 0.00 AC: 0 AN: 3928

South Asian (SAS) AF: 0.00 AC: 0 AN: 17390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1652

European-Non Finnish (NFE) AF: 0.00000130 AC: 1 AN: 768530

Other (OTH) AF: 0.00 AC: 0 AN: 27852

GnomAD4 genome AF: 0.000894 AC: 131 AN: 146554 Hom.: 2 Cov.: 32 AF XY: 0.000967 AC XY: 69 AN XY: 71370

African (AFR) AF: 0.00308 AC: 126 AN: 40960

American (AMR) AF: 0.000271 AC: 4 AN: 14786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65812

Other (OTH) AF: 0.000490 AC: 1 AN: 2042

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.000933

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.90
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.0030
Sift	Uncertain	0.015	D
Sift4G	Benign	0.53	T
Polyphen		0.0080	B
Vest4		0.088
MutPred		0.25		Gain of phosphorylation at A24 (P = 0.0012)
MVP		0.27
MPC		1.8
ClinPred		0.041	T
GERP RS		0.63
PromoterAI		-0.012	Neutral
Varity_R		0.049
gMVP		0.20
Mutation Taster		=93/7	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: rs956704380; hg19: chr4-7194443;