1-103571747-C-A

Variant names:

• chr1-103571747-C-A
• NM_001387437.1:c.145C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001387437.1(AMY2B):​c.145C>A​(p.Pro49Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000617 in 1,459,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P49S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: AMY2B NM_001387437.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMY2B	NM_001387437.1	c.145C>A	p.Pro49Thr	missense_variant	Exon 1 of 10	ENST00000684275.1	NP_001374366.1
AMY2B	NM_001386109.1	c.145C>A	p.Pro49Thr	missense_variant	Exon 3 of 12		NP_001373038.1
AMY2B	NM_020978.4	c.145C>A	p.Pro49Thr	missense_variant	Exon 3 of 12		NP_066188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMY2B	ENST00000684275.1	c.145C>A	p.Pro49Thr	missense_variant	Exon 1 of 10		NM_001387437.1	ENSP00000507176.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1459652 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726130

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.145C>A (p.P49T) alteration is located in exon 3 (coding exon 1) of the AMY2B gene. This alteration results from a C to A substitution at nucleotide position 145, causing the proline (P) at amino acid position 49 to be replaced by a threonine (T). 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	0.19
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;.;.;H
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.8	D;D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.73
MutPred		0.80		Loss of ubiquitination at K50 (P = 0.0594);Loss of ubiquitination at K50 (P = 0.0594);Loss of ubiquitination at K50 (P = 0.0594);Loss of ubiquitination at K50 (P = 0.0594);
MVP		0.97
MPC		0.60
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.84
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-104114369;