8-39746584-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001464.5(ADAM2):​c.2062C>G​(p.Pro688Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000566 in 1,606,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ADAM2
NM_001464.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.42

Publications

1 publications found
Variant links:
Genes affected
ADAM2 (HGNC:198): (ADAM metallopeptidase domain 2) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded protein is a subunit of an integral sperm membrane glycoprotein called fertilin, which plays an important role in sperm-egg interactions. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13554668).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAM2NM_001464.5 linkc.2062C>G p.Pro688Ala missense_variant Exon 19 of 21 ENST00000265708.9 NP_001455.3 Q99965-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAM2ENST00000265708.9 linkc.2062C>G p.Pro688Ala missense_variant Exon 19 of 21 1 NM_001464.5 ENSP00000265708.4 Q99965-1
ADAM2ENST00000347580.8 linkc.2005C>G p.Pro669Ala missense_variant Exon 18 of 20 1 ENSP00000343854.4 Q99965-2
ADAM2ENST00000379853.6 linkc.1594C>G p.Pro532Ala missense_variant Exon 15 of 17 1 ENSP00000369182.2 Q6P2G0
ADAM2ENST00000521880.5 linkc.1873C>G p.Pro625Ala missense_variant Exon 18 of 20 2 ENSP00000429352.1 B4DWY7

Frequencies

GnomAD3 genomes
AF:
0.000362
AC:
55
AN:
151974
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00123
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000691
AC:
17
AN:
245870
AF XY:
0.0000527
show subpopulations
Gnomad AFR exome
AF:
0.00107
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000247
AC:
36
AN:
1454594
Hom.:
0
Cov.:
30
AF XY:
0.0000166
AC XY:
12
AN XY:
723656
show subpopulations
African (AFR)
AF:
0.000878
AC:
29
AN:
33026
American (AMR)
AF:
0.00
AC:
0
AN:
43860
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26016
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39258
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84846
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53192
Middle Eastern (MID)
AF:
0.000174
AC:
1
AN:
5750
European-Non Finnish (NFE)
AF:
9.02e-7
AC:
1
AN:
1108542
Other (OTH)
AF:
0.0000832
AC:
5
AN:
60104
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000362
AC:
55
AN:
152092
Hom.:
0
Cov.:
32
AF XY:
0.000377
AC XY:
28
AN XY:
74336
show subpopulations
African (AFR)
AF:
0.00123
AC:
51
AN:
41494
American (AMR)
AF:
0.000196
AC:
3
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10560
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67984
Other (OTH)
AF:
0.00
AC:
0
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
3
6
10
13
16
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.000276
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000824
AC:
10

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 03, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2062C>G (p.P688A) alteration is located in exon 19 (coding exon 19) of the ADAM2 gene. This alteration results from a C to G substitution at nucleotide position 2062, causing the proline (P) at amino acid position 688 to be replaced by an alanine (A). 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
0.15
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
6.3
DANN
Benign
0.39
DEOGEN2
Benign
0.051
.;.;T;T;T
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.39
FATHMM_MKL
Benign
0.62
D
LIST_S2
Benign
0.79
T;T;T;T;.
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.14
T;T;T;T;T
MetaSVM
Benign
-0.36
T
MutationAssessor
Benign
1.7
.;.;L;.;.
PhyloP100
1.4
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-2.1
N;N;N;.;N
REVEL
Uncertain
0.30
Sift
Benign
0.80
T;T;T;.;T
Sift4G
Benign
1.0
T;T;T;T;T
Polyphen
0.36
B;D;B;B;B
Vest4
0.54
MVP
0.95
MPC
0.035
ClinPred
0.032
T
GERP RS
2.7
Varity_R
0.030
gMVP
0.30
Mutation Taster
=85/15
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs151129845; hg19: chr8-39604103; COSMIC: COSV55862874; API