dbSNP rs200534841: ADAM2:p.Glu725* (chr8-39746473-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001464.5(ADAM2):c.2173G>T(p.Glu725*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,401,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ADAM2
NM_001464.5 stop_gained, splice_region

Scores

Splicing: ADA: 0.9778

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

Publications

2 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:

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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.2173G>T	p.Glu725*	stop_gained, splice_region_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.2173G>T	p.Glu725*	stop_gained, splice_region_variant	Exon 19 of 21	1	NM_001464.5	ENSP00000265708.4	Q99965-1
ADAM2	ENST00000347580.8 link	c.2116G>T	p.Glu706*	stop_gained, splice_region_variant	Exon 18 of 20	1		ENSP00000343854.4	Q99965-2
ADAM2	ENST00000379853.6 link	c.1705G>T	p.Glu569*	stop_gained, splice_region_variant	Exon 15 of 17	1		ENSP00000369182.2	Q6P2G0
ADAM2	ENST00000521880.5 link	c.1984G>T	p.Glu662*	stop_gained, splice_region_variant	Exon 18 of 20	2		ENSP00000429352.1	B4DWY7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000478

AC:

AN:

209214

AF XY:

0.00

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:

0.00000985

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1401856

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697608

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29830

American (AMR)

AF:

0.00

AC:

AN:

32336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24204

East Asian (EAS)

AF:

0.00

AC:

AN:

37670

South Asian (SAS)

AF:

0.00

AC:

AN:

76548

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5124

European-Non Finnish (NFE)

AF:

9.21e-7

AC:

AN:

1086036

Other (OTH)

AF:

0.00

AC:

AN:

57826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.83

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.80

PhyloP100

2.8

Vest4

0.58

GERP RS

3.9

Mutation Taster

=61/139

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.35

Position offset: -1

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

Publications

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rs200534841

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over