chr11-130903366-G-A

Position:

• chr11-130903366-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014758.3(SNX19):​c.2462C>T​(p.Ala821Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,274 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: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SNX19 NM_014758.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.89

Genes affected

SNX19 (HGNC:21532): (sorting nexin 19) Islet antigen-2 (IA-2) is an autoantigen in type 1 diabetes and plays a role in insulin secretion. IA-2 is found in dense-core secretory vesicles and interacts with the product of this gene, a sorting nexin. In mouse pancreatic beta-cells, the encoded protein influenced insulin secretion by stabilizing the number of dense-core secretory vesicles. [provided by RefSeq, Dec 2016]

SNX19 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNX19	NM_014758.3	c.2462C>T	p.Ala821Val	missense_variant	8/11	ENST00000265909.9	NP_055573.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNX19	ENST00000265909.9	c.2462C>T	p.Ala821Val	missense_variant	8/11	1	NM_014758.3	ENSP00000265909.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460274 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726480

Gnomad4 AFR exome AF: 0.0000598

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: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 31

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

Sep 16, 2021

The c.2462C>T (p.A821V) alteration is located in exon 8 (coding exon 8) of the SNX19 gene. This alteration results from a C to T substitution at nucleotide position 2462, causing the alanine (A) at amino acid position 821 to be replaced by a valine (V). 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	0.43
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.012	T;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T;.;T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.81	L;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.012	D;T;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.65
MutPred		0.58		Loss of disorder (P = 0.0643);.;.;.;
MVP		0.91
MPC		0.53
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.26
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1945399179; hg19: chr11-130773261;