chr8-39746577-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001464.5(ADAM2):c.2069T>C(p.Phe690Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,607,168 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ADAM2
NM_001464.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.360

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]

ADAM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM2	NM_001464.5 link	c.2069T>C	p.Phe690Ser	missense_variant	Exon 19 of 21	ENST00000265708.9	NP_001455.3	Q99965-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAM2	ENST00000265708.9 link	c.2069T>C	p.Phe690Ser	missense_variant	Exon 19 of 21	1	NM_001464.5	ENSP00000265708.4	Q99965-1
ADAM2	ENST00000347580.8 link	c.2012T>C	p.Phe671Ser	missense_variant	Exon 18 of 20	1		ENSP00000343854.4	Q99965-2
ADAM2	ENST00000379853.6 link	c.1601T>C	p.Phe534Ser	missense_variant	Exon 15 of 17	1		ENSP00000369182.2	Q6P2G0
ADAM2	ENST00000521880.5 link	c.1880T>C	p.Phe627Ser	missense_variant	Exon 18 of 20	2		ENSP00000429352.1	B4DWY7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152184

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000406

AC:

AN:

246382

AF XY:

0.00000751

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1454984

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

723858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33090

American (AMR)

AF:

0.00

AC:

AN:

43876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39320

South Asian (SAS)

AF:

0.00

AC:

AN:

84904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000262

AC:

AN:

1108670

Other (OTH)

AF:

0.0000333

AC:

AN:

60118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.033899), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000588

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2069T>C (p.F690S) alteration is located in exon 19 (coding exon 19) of the ADAM2 gene. This alteration results from a T to C substitution at nucleotide position 2069, causing the phenylalanine (F) at amino acid position 690 to be replaced by a serine (S). 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

Uncertain

0.37

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;.;T;T;T

Eigen

Benign

-0.0050

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.72

T;T;T;T;.

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.64

D;D;D;D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

1.7

.;.;L;.;.

PhyloP100

0.36

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.5

D;D;D;.;D

REVEL

Uncertain

0.54

Sift

Benign

0.22

T;T;T;.;T

Sift4G

Benign

0.21

T;T;T;T;T

Polyphen

1.0

D;D;P;D;D

Vest4

0.55

MutPred

0.45

.;.;Gain of glycosylation at F690 (P = 0.0296);.;.;

MVP

0.94

MPC

0.071

ClinPred

0.54

GERP RS

2.4

Varity_R

0.13

gMVP

0.56

Mutation Taster

=57/43

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr8-39746577-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over