4-7192827-C-T

Variant names:

• chr4-7192827-C-T
• NM_020777.3:c.181C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020777.3(SORCS2):​c.181C>T​(p.His61Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 888,370 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H61R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.10
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060007304).

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.181C>T	p.His61Tyr	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.181C>T	p.His61Tyr	missense	Exon 1 of 27	ENSP00000422185.2	Q96PQ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000180 AC: 16 AN: 888370 Hom.: 0 Cov.: 30 AF XY: 0.0000145 AC XY: 6 AN XY: 414994

African (AFR) AF: 0.00 AC: 0 AN: 16916

American (AMR) AF: 0.00 AC: 0 AN: 2802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6608

East Asian (EAS) AF: 0.000154 AC: 1 AN: 6474

South Asian (SAS) AF: 0.00 AC: 0 AN: 17826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1870

European-Non Finnish (NFE) AF: 0.0000188 AC: 15 AN: 798702

Other (OTH) AF: 0.00 AC: 0 AN: 30540

GnomAD4 genome Cov.: 32

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	0.081
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.0040
Sift	Benign	0.24	T
Sift4G	Benign	0.26	T
Polyphen		0.023	B
Vest4		0.14
MutPred		0.24		Gain of phosphorylation at H61 (P = 0.0123)
MVP		0.57
MPC		2.1
ClinPred		0.060	T
GERP RS		-2.7
PromoterAI		0.038	Neutral
Varity_R		0.039
gMVP		0.19
Mutation Taster		=97/3	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

hg19: chr4-7194554;