chr18-907724-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001099733.2(ADCYAP1):c.176C>G(p.Pro59Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000684 in 1,535,012 control chromosomes in the GnomAD database, including 1 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 0.000059 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000069 ( 1 hom. )

Consequence

ADCYAP1
NM_001099733.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25

Variant links:

Genes affected

ADCYAP1 (HGNC:241): (adenylate cyclase activating polypeptide 1) This gene encodes a secreted proprotein that is further processed into multiple mature peptides. These peptides stimulate adenylate cyclase and increase cyclic adenosine monophosphate (cAMP) levels, resulting in the transcriptional activation of target genes. The products of this gene are key mediators of neuroendocrine stress responses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

ADCYAP1 links:

ENSG00000265671 (HGNC:):

ENSG00000265671 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15509179).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCYAP1	NM_001099733.2 link	c.176C>G	p.Pro59Arg	missense_variant	Exon 3 of 5	ENST00000450565.8	NP_001093203.1	P18509
ADCYAP1	NM_001117.5 link	c.176C>G	p.Pro59Arg	missense_variant	Exon 2 of 4		NP_001108.2	P18509
ADCYAP1	XM_005258081.5 link	c.593C>G	p.Pro198Arg	missense_variant	Exon 4 of 6		XP_005258138.2	B7Z222
ADCYAP1	XM_047437288.1 link	c.176C>G	p.Pro59Arg	missense_variant	Exon 3 of 5		XP_047293244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADCYAP1	ENST00000450565.8 link	c.176C>G	p.Pro59Arg	missense_variant	Exon 3 of 5	1	NM_001099733.2	ENSP00000411658.3	P18509
ADCYAP1	ENST00000579794.1 link	c.176C>G	p.Pro59Arg	missense_variant	Exon 2 of 4	1		ENSP00000462647.1	P18509
ADCYAP1	ENST00000269200.5 link	n.174C>G		non_coding_transcript_exon_variant	Exon 1 of 3	2
ENSG00000265671	ENST00000582554.1 link	n.-44G>C		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152108

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000135

AC:

AN:

133618

Hom.:

AF XY:

0.000108

AC XY:

AN XY:

74000

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000396

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000694

AC:

AN:

1382796

Hom.:

Cov.:

AF XY:

0.0000863

AC XY:

AN XY:

683648

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000848

Gnomad4 SAS exome

AF:

0.000607

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000380

Gnomad4 OTH exome

AF:

0.0000521

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74420

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:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000302

ExAC

AF:

0.0000914

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.176C>G (p.P59R) alteration is located in exon 3 (coding exon 2) of the ADCYAP1 gene. This alteration results from a C to G substitution at nucleotide position 176, causing the proline (P) at amino acid position 59 to be replaced by an arginine (R). 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

0.081

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.72

.;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Benign

0.37

REVEL

Benign

0.068

Sift4G

Benign

0.45

T;T

Polyphen

0.97

D;D

Vest4

0.27

MutPred

0.24

Gain of methylation at P59 (P = 0.0141);Gain of methylation at P59 (P = 0.0141);

MVP

0.82

MPC

1.4

ClinPred

0.34

GERP RS

3.6

Varity_R

0.036

gMVP

0.42

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