4-7192654-A-T

Variant names:

• chr4-7192654-A-T
• rs1379531032
• NM_020777.3:c.8A>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.8A>T​(p.His3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000238 in 839,952 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.542
• 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=0.038533658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3	c.8A>T	p.His3Leu	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.8A>T	p.His3Leu	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000238 AC: 2 AN: 839952 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 388612

African (AFR) AF: 0.00 AC: 0 AN: 15890

American (AMR) AF: 0.00 AC: 0 AN: 1204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5290

East Asian (EAS) AF: 0.00 AC: 0 AN: 3800

South Asian (SAS) AF: 0.00 AC: 0 AN: 17330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1638

European-Non Finnish (NFE) AF: 0.00000261 AC: 2 AN: 766260

Other (OTH) AF: 0.00 AC: 0 AN: 27644

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.83
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.54
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.051
Sift	Benign	1.0	T
Sift4G	Uncertain	0.039	D
Polyphen		0.0	B
Vest4		0.071
MutPred		0.34		Loss of solvent accessibility (P = 0.0052);
MVP		0.43
MPC		2.2
ClinPred		0.052	T
GERP RS		-4.7
PromoterAI		0.013	Neutral
Varity_R		0.090
gMVP		0.23
Mutation Taster		=85/15	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: rs1379531032; hg19: chr4-7194381;