Genetic Variant AMY2B:p.Arg25Gln (chr1-103571676-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001387437.1(AMY2B):c.74G>A(p.Arg25Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,611,864 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00088 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

AMY2B
NM_001387437.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.24

Variant links:

Genes affected

AMY2B (HGNC:478): (amylase alpha 2B) Amylases are secreted proteins that hydrolyze 1,4-alpha-glucoside bonds in oligosaccharides and polysaccharides, and thus catalyze the first step in digestion of dietary starch and glycogen. The human genome has a cluster of several amylase genes that are expressed at high levels in either salivary gland or pancreas. This gene encodes an amylase isoenzyme produced by the pancreas. [provided by RefSeq, Jun 2013]

AMY2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024542063).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMY2B	NM_001387437.1 link	c.74G>A	p.Arg25Gln	missense_variant	Exon 1 of 10	ENST00000684275.1	NP_001374366.1
AMY2B	NM_001386109.1 link	c.74G>A	p.Arg25Gln	missense_variant	Exon 3 of 12		NP_001373038.1
AMY2B	NM_020978.4 link	c.74G>A	p.Arg25Gln	missense_variant	Exon 3 of 12		NP_066188.1	P19961-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMY2B	ENST00000684275.1 link	c.74G>A	p.Arg25Gln	missense_variant	Exon 1 of 10		NM_001387437.1	ENSP00000507176.1		P19961-1

Frequencies

GnomAD3 genomes

AF:

0.000881

AC:

134

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

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:

0.000755

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000992

AC:

248

AN:

249914

Hom.:

AF XY:

0.000976

AC XY:

132

AN XY:

135302

show subpopulations

Gnomad AFR exome

AF:

0.000568

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000742

Gnomad NFE exome

AF:

0.00190

Gnomad OTH exome

AF:

0.000494

GnomAD4 exome

AF:

0.00117

AC:

1713

AN:

1459644

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

828

AN XY:

726124

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000861

Gnomad4 NFE exome

AF:

0.00145

Gnomad4 OTH exome

AF:

0.000664

GnomAD4 genome

AF:

0.000880

AC:

134

AN:

152220

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000755

Gnomad4 NFE

AF:

0.00165

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.000748

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00126

AC:

153

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.74G>A (p.R25Q) alteration is located in exon 3 (coding exon 1) of the AMY2B gene. This alteration results from a G to A substitution at nucleotide position 74, causing the arginine (R) at amino acid position 25 to be replaced by a glutamine (Q). 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

Benign

0.18

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;.;.;D

Eigen

Benign

-0.036

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.93

.;D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.025

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Pathogenic

3.3

M;.;.;M

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.9

D;D;D;.

REVEL

Benign

0.17

Sift

Uncertain

0.015

D;D;D;.

Sift4G

Uncertain

0.025

D;D;D;D

Polyphen

0.89

P;.;.;P

Vest4

0.24

MVP

0.72

MPC

0.34

ClinPred

0.086

GERP RS

1.9

Varity_R

0.31

gMVP

0.71

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