11-130903262-C-A

Variant names:

• chr11-130903262-C-A
• rs138056272
• NM_014758.3:c.2566G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014758.3(SNX19):​c.2566G>T​(p.Val856Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 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. V856I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SNX19 NM_014758.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 1 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

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.2566G>T	p.Val856Phe	missense	Exon 8 of 11	NP_055573.3	Q92543-1
	SNX19	NM_001347918.2		c.2446G>T	p.Val816Phe	missense	Exon 7 of 10	NP_001334847.2
	SNX19	NM_001347919.2		c.2566G>T	p.Val856Phe	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.2566G>T	p.Val856Phe	missense	Exon 8 of 11	ENSP00000265909.4	Q92543-1
	SNX19	ENST00000534726.5	TSL:1	c.286G>T	p.Val96Phe	missense	Exon 4 of 7	ENSP00000433699.1	E9PJV7
	SNX19	ENST00000528555.5	TSL:2	c.706G>T	p.Val236Phe	missense	Exon 8 of 11	ENSP00000435122.1	E9PLV3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461404 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727022

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111662

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.0090
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.7
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.84	P
Vest4		0.72
MutPred		0.74		Loss of MoRF binding (P = 0.101)
MVP		0.40
MPC		0.45
ClinPred		0.91	D
GERP RS		3.7
Varity_R		0.49
gMVP		0.76
Mutation Taster		=81/19	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: rs138056272; hg19: chr11-130773157;