11-130903346-G-A

Variant names:

• chr11-130903346-G-A
• rs144457394
• NM_014758.3:c.2482C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014758.3(SNX19):​c.2482C>T​(p.Leu828Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,962 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L828V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SNX19 NM_014758.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014758.3. 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
	SNX19	NM_014758.3	MANE Select	c.2482C>T	p.Leu828Phe	missense	Exon 8 of 11	NP_055573.3	Q92543-1
	SNX19	NM_001347918.2		c.2362C>T	p.Leu788Phe	missense	Exon 7 of 10	NP_001334847.2
	SNX19	NM_001347919.2		c.2482C>T	p.Leu828Phe	missense	Exon 8 of 10	NP_001334848.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNX19	ENST00000265909.9	TSL:1 MANE Select	c.2482C>T	p.Leu828Phe	missense	Exon 8 of 11	ENSP00000265909.4	Q92543-1
	SNX19	ENST00000534726.5	TSL:1	c.202C>T	p.Leu68Phe	missense	Exon 4 of 7	ENSP00000433699.1	E9PJV7
	SNX19	ENST00000528555.5	TSL:2	c.622C>T	p.Leu208Phe	missense	Exon 8 of 11	ENSP00000435122.1	E9PLV3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460962 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726822

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5162

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111874

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0052	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.29
Sift	Benign	0.076	T
Sift4G	Uncertain	0.013	D
Polyphen		0.96	D
Vest4		0.41
MutPred		0.61		Loss of stability (P = 0.0325)
MVP		0.80
MPC		0.47
ClinPred		0.69	D
GERP RS		2.6
Varity_R		0.032
gMVP		0.49
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144457394; hg19: chr11-130773241;