8-39749323-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001464.5(ADAM2):​c.2003C>T​(p.Ala668Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,610,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ADAM2
NM_001464.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.27
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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06028551).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADAM2NM_001464.5 linkc.2003C>T p.Ala668Val missense_variant Exon 18 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.2003C>T p.Ala668Val missense_variant Exon 18 of 21 1 NM_001464.5 ENSP00000265708.4 Q99965-1
ADAM2ENST00000347580.8 linkc.1946C>T p.Ala649Val missense_variant Exon 17 of 20 1 ENSP00000343854.4 Q99965-2
ADAM2ENST00000379853.6 linkc.1535C>T p.Ala512Val missense_variant Exon 14 of 17 1 ENSP00000369182.2 Q6P2G0
ADAM2ENST00000521880.5 linkc.1814C>T p.Ala605Val missense_variant Exon 17 of 20 2 ENSP00000429352.1 B4DWY7

Frequencies

GnomAD3 genomes
AF:
0.0000659
AC:
10
AN:
151718
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000242
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250236
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135266
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00
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
AF:
0.00000754
AC:
11
AN:
1458992
Hom.:
0
Cov.:
31
AF XY:
0.00000964
AC XY:
7
AN XY:
725858
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
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:
0.00
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.0000659
AC:
10
AN:
151838
Hom.:
0
Cov.:
32
AF XY:
0.0000943
AC XY:
7
AN XY:
74212
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.00
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:
0.0000712
Hom.:
0
Bravo
AF:
0.0000756
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 18, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2003C>T (p.A668V) alteration is located in exon 18 (coding exon 18) of the ADAM2 gene. This alteration results from a C to T substitution at nucleotide position 2003, causing the alanine (A) at amino acid position 668 to be replaced by a valine (V). 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
0.089
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
0.0050
DANN
Benign
0.61
DEOGEN2
Benign
0.022
.;.;T;T;T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.9
FATHMM_MKL
Benign
0.0034
N
LIST_S2
Benign
0.43
T;T;T;T;.
M_CAP
Benign
0.0011
T
MetaRNN
Benign
0.060
T;T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.0
.;.;N;.;.
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.69
N;N;N;.;N
REVEL
Benign
0.011
Sift
Benign
0.31
T;T;T;.;T
Sift4G
Benign
0.30
T;T;T;T;T
Polyphen
0.0010
B;B;B;B;B
Vest4
0.19
MVP
0.17
MPC
0.023
ClinPred
0.029
T
GERP RS
-4.7
Varity_R
0.021
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs376114634; hg19: chr8-39606842; API