Variant chr1-103619721-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000699.4(AMY2A):c.681C>A(p.Asp227Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000447 in 151,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000038 ( 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: -1.22

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_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.084721744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMY2A	NM_000699.4 link	c.681C>A	p.Asp227Glu	missense_variant	4/10	ENST00000414303.7	NP_000690.1	P04746-1Q53F26
AMY2A	XM_047418085.1 link	c.681C>A	p.Asp227Glu	missense_variant	5/11		XP_047274041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMY2A	ENST00000414303.7 link	c.681C>A	p.Asp227Glu	missense_variant	4/10	1	NM_000699.4	ENSP00000397582.2		P04746-1
AMY2A	ENST00000423678.2 link	c.513+613C>A		intron_variant		3		ENSP00000390832.2		H7BZQ8

Frequencies

GnomAD3 genomes

AF:

0.000448

AC:

AN:

151844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

124652

Hom.:

AF XY:

0.0000463

AC XY:

AN XY:

64818

show subpopulations

Gnomad AFR exome

AF:

0.000575

Gnomad AMR exome

AF:

0.0000519

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000383

AC:

AN:

1461300

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.00147

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000447

AC:

AN:

151962

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000338

Hom.:

ExAC

AF:

0.00000903

AC:

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

Aug 26, 2024

The c.681C>A (p.D227E) alteration is located in exon 4 (coding exon 4) of the AMY2A gene. This alteration results from a C to A substitution at nucleotide position 681, causing the aspartic acid (D) at amino acid position 227 to be replaced by a glutamic acid (E). 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

0.14

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.31

CADD

Benign

8.2

DANN

Benign

0.96

DEOGEN2

Uncertain

0.54

D;D

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.78

T;.

M_CAP

Benign

0.070

MetaRNN

Benign

0.085

T;T

MetaSVM

Uncertain

0.025

MutationAssessor

Benign

1.7

L;L

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.4

.;N

REVEL

Benign

0.24

Sift

Benign

0.048

.;D

Sift4G

Benign

0.12

T;T

Polyphen

0.0

B;B

Vest4

0.18

MutPred

0.36

Gain of methylation at K223 (P = 0.1655);Gain of methylation at K223 (P = 0.1655);

MVP

0.47

MPC

1.7

ClinPred

0.016

GERP RS

-1.2

Varity_R

0.42

gMVP

0.25

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