4-7396317-C-G

Position:

• chr4-7396317-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020777.3(SORCS2):​c.510C>G​(p.His170Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SORCS2 NM_020777.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.31

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35334998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORCS2	NM_020777.3	c.510C>G	p.His170Gln	missense_variant	2/27	ENST00000507866.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORCS2	ENST00000507866.6	c.510C>G	p.His170Gln	missense_variant	2/27	1	NM_020777.3	P1
SORCS2	ENST00000511199.1	n.125C>G		non_coding_transcript_exon_variant	2/6	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

The c.510C>G (p.H170Q) alteration is located in exon 2 (coding exon 2) of the SORCS2 gene. This alteration results from a C to G substitution at nucleotide position 510, causing the histidine (H) at amino acid position 170 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0080	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.27
Sift	Benign	0.090	T
Sift4G	Benign	0.088	T
Polyphen		1.0	D
Vest4		0.55
MutPred		0.34		Gain of sheet (P = 0.0149);
MVP		0.38
MPC		0.63
ClinPred		0.89	D
GERP RS		-6.0
Varity_R		0.13
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-7398044;