5-122775123-C-G

Position:

• chr5-122775123-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_003100.4(SNX2):​c.20C>G​(p.Pro7Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000486 in 1,440,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: SNX2 NM_003100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

Genes affected

SNX2 (HGNC:11173): (sorting nexin 2) This gene belongs to the sorting nexin family whose members contain the phosphoinositide-binding phox (PX) domain. The encoded protein is a component of the retromer complex which plays a role in protein sorting in the endocytic pathway. This protein may form oligomeric complexes with other family members. Alternate splicing results in multiple transcript variants of this gene. Pseudogenes associated with this gene are located on chromosomes 1 and 7. [provided by RefSeq, May 2013]

SNX2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNX2	NM_003100.4	c.20C>G	p.Pro7Arg	missense_variant	1/15	ENST00000379516.7	NP_003091.2
SNX2	NM_001278199.1	c.-883C>G		5_prime_UTR_variant	1/15		NP_001265128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNX2	ENST00000379516.7	c.20C>G	p.Pro7Arg	missense_variant	1/15	1	NM_003100.4	ENSP00000368831.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000486 AC: 7 AN: 1440170 Hom.: 0 Cov.: 29 AF XY: 0.00000420 AC XY: 3 AN XY: 713846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000634

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

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

Feb 21, 2024

The c.20C>G (p.P7R) alteration is located in exon 1 (coding exon 1) of the SNX2 gene. This alteration results from a C to G substitution at nucleotide position 20, causing the proline (P) at amino acid position 7 to be replaced by an arginine (R). 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	0.34
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.015	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.65
MutPred		0.66		Loss of catalytic residue at P7 (P = 0.0171);Loss of catalytic residue at P7 (P = 0.0171);
MVP		0.62
MPC		0.76
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.63
gMVP		0.57

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: rs957416964; hg19: chr5-122110818;