4-7654128-C-T

Variant names:

• chr4-7654128-C-T
• rs2285789
• NM_020777.3:c.814-6C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020777.3(SORCS2):​c.814-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.688 in 1,567,860 control chromosomes in the GnomAD database, including 383,421 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.57 (29196 hom., cov: 34)
  • Exomes 𝑓: 0.70 (354225 hom.)
• Consequence: SORCS2 NM_020777.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001637
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.673
• Publications: 21 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]

ENSG00000299251 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3	c.814-6C>T		splice_region_variant, intron_variant	Intron 4 of 26	ENST00000507866.6	NP_065828.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS2	ENST00000507866.6	c.814-6C>T		splice_region_variant, intron_variant	Intron 4 of 26	1	NM_020777.3	ENSP00000422185.2
ENSG00000299251	ENST00000761945.1	n.2G>A		non_coding_transcript_exon_variant	Exon 1 of 2
SORCS2	ENST00000511199.1	n.429-6C>T		splice_region_variant, intron_variant	Intron 4 of 5	4
ENSG00000299251	ENST00000761946.1	n.-5G>A		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86720 AN: 152014 Hom.: 29180 Cov.: 34

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.588

GnomAD2 exomes AF: 0.664 AC: 122284 AN: 184260 AF XY: 0.662

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.878

Gnomad FIN exome AF: 0.733

Gnomad NFE exome AF: 0.685

Gnomad OTH exome AF: 0.674

GnomAD4 exome AF: 0.701 AC: 991835 AN: 1415728 Hom.: 354225 Cov.: 39 AF XY: 0.698 AC XY: 488388 AN XY: 699840

African (AFR) AF: 0.165 AC: 5439 AN: 32872

American (AMR) AF: 0.728 AC: 27420 AN: 37642

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 16972 AN: 25418

East Asian (EAS) AF: 0.866 AC: 32330 AN: 37314

South Asian (SAS) AF: 0.606 AC: 48863 AN: 80632

European-Finnish (FIN) AF: 0.736 AC: 37282 AN: 50632

Middle Eastern (MID) AF: 0.623 AC: 3555 AN: 5708

European-Non Finnish (NFE) AF: 0.718 AC: 780307 AN: 1086716

Other (OTH) AF: 0.675 AC: 39667 AN: 58794

GnomAD4 genome AF: 0.570 AC: 86743 AN: 152132 Hom.: 29196 Cov.: 34 AF XY: 0.575 AC XY: 42773 AN XY: 74376

African (AFR) AF: 0.187 AC: 7763 AN: 41506

American (AMR) AF: 0.687 AC: 10509 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2363 AN: 3470

East Asian (EAS) AF: 0.883 AC: 4533 AN: 5136

South Asian (SAS) AF: 0.611 AC: 2948 AN: 4822

European-Finnish (FIN) AF: 0.747 AC: 7922 AN: 10606

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.715 AC: 48616 AN: 67984

Other (OTH) AF: 0.592 AC: 1250 AN: 2112

Alfa AF: 0.658 Hom.: 121292

Bravo AF: 0.553

Asia WGS AF: 0.704 AC: 2448 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.0
DANN	Benign	0.46
PhyloP100		0.67
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.010
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: rs2285789; hg19: chr4-7655855;