Variant 1-103619585-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong

The NM_000699.4(AMY2A):c.545A>G(p.Asp182Gly) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AMY2A
NM_000699.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.80

Variant links:

Genes affected

AMY2A (HGNC:477): (amylase alpha 2A) This gene encodes a member of the alpha-amylase family of proteins. Amylases are secreted proteins that hydrolyze 1,4-alpha-glucoside bonds in oligosaccharides and polysaccharides, catalyzing the first step in digestion of dietary starch and glycogen. This gene and several family members are present in a gene cluster on chromosome 1. This gene encodes an amylase isoenzyme produced by the pancreas. [provided by RefSeq, Jan 2015]

AMY2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity AMYP_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMY2A	NM_000699.4 linkuse as main transcript	c.545A>G	p.Asp182Gly	missense_variant	4/10	ENST00000414303.7	NP_000690.1
AMY2A	XM_047418085.1 linkuse as main transcript	c.545A>G	p.Asp182Gly	missense_variant	5/11		XP_047274041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMY2A	ENST00000414303.7 linkuse as main transcript	c.545A>G	p.Asp182Gly	missense_variant	4/10	1	NM_000699.4	ENSP00000397582	P1	P04746-1
AMY2A	ENST00000423678.2 linkuse as main transcript	c.513+477A>G		intron_variant		3		ENSP00000390832

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000753

AC:

AN:

1461080

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726884

show subpopulations

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:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000132

AC:

AN:

151184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73760

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000296

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.545A>G (p.D182G) alteration is located in exon 4 (coding exon 4) of the AMY2A gene. This alteration results from a A to G substitution at nucleotide position 545, causing the aspartic acid (D) at amino acid position 182 to be replaced by a glycine (G). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;.

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

H;H

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.2

.;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.98

D;D

Vest4

0.94

MutPred

0.92

Loss of ubiquitination at K187 (P = 0.0574);Loss of ubiquitination at K187 (P = 0.0574);

MVP

0.98

MPC

4.1

ClinPred

0.99

GERP RS

3.0

Varity_R

0.99

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over