10-106579159-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_052918.5(SORCS1):c.3371+210A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,614,072 control chromosomes in the GnomAD database, including 2,201 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.039 (315 hom., cov: 32)
  • Exomes 𝑓: 0.019 (1886 hom.)
• Consequence: SORCS1 NM_052918.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0930

Genes affected

SORCS1 (HGNC:16697): (sortilin related VPS10 domain containing receptor 1) 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. Two of the five family members (sortilin and sortilin-related receptor) are synthesized as preproproteins; it is not yet known if this encoded protein is also a preproprotein. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029719472).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORCS1	NM_052918.5	c.3371+210A>G		intron_variant		ENST00000263054.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORCS1	ENST00000263054.11	c.3371+210A>G		intron_variant		1	NM_052918.5	P1
SORCS1	ENST00000369698.6	c.2198A>G	p.Asn733Ser	missense_variant	18/19	5
SORCS1	ENST00000452214.5	c.509A>G	p.Asn170Ser	missense_variant	5/6	3
SORCS1	ENST00000473866.1	n.352A>G		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5932 AN: 152116 Hom.: 315 Cov.: 32

Gnomad AFR AF: 0.0513

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0955

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.0717

Gnomad FIN AF: 0.0362

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0513 AC: 12905 AN: 251332 Hom.: 998 AF XY: 0.0468 AC XY: 6352 AN XY: 135824

Gnomad AFR exome AF: 0.0520

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.257

Gnomad SAS exome AF: 0.0572

Gnomad FIN exome AF: 0.0299

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.0325

GnomAD4 exome AF: 0.0187 AC: 27301 AN: 1461836 Hom.: 1886 Cov.: 31 AF XY: 0.0191 AC XY: 13917 AN XY: 727220

Gnomad4 AFR exome AF: 0.0510

Gnomad4 AMR exome AF: 0.116

Gnomad4 ASJ exome AF: 0.0303

Gnomad4 EAS exome AF: 0.247

Gnomad4 SAS exome AF: 0.0567

Gnomad4 FIN exome AF: 0.0283

Gnomad4 NFE exome AF: 0.00138

Gnomad4 OTH exome AF: 0.0293

GnomAD4 genome AF: 0.0390 AC: 5936 AN: 152236 Hom.: 315 Cov.: 32 AF XY: 0.0436 AC XY: 3249 AN XY: 74438

Gnomad4 AFR AF: 0.0513

Gnomad4 AMR AF: 0.0956

Gnomad4 ASJ AF: 0.0306

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.0718

Gnomad4 FIN AF: 0.0362

Gnomad4 NFE AF: 0.00223

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.0103 Hom.: 179

Bravo AF: 0.0439

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.0572 AC: 252

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.0457 AC: 5555

Asia WGS AF: 0.135 AC: 467 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00267

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	5.9
Dann	Benign	0.67
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.57	T;T;T
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.21	T
Sift4G	Benign	0.43	T;T;T
Vest4		0.027
MPC		0.20
ClinPred		0.0034	T
GERP RS		-6.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs11192966; hg19: chr10-108338917; COSMIC: COSV53882908;