8-39744870-G-C

Variant names:

• chr8-39744870-G-C
• rs144646998
• NM_001464.5:c.2198C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001464.5(ADAM2):​c.2198C>G​(p.Pro733Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P733H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADAM2 NM_001464.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.509
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08974558).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001464.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM2	NM_001464.5	MANE Select	c.2198C>G	p.Pro733Arg	missense	Exon 20 of 21	NP_001455.3
	ADAM2	NM_001278113.2		c.2141C>G	p.Pro714Arg	missense	Exon 19 of 20	NP_001265042.1	Q99965-2
	ADAM2	NM_001278114.2		c.2009C>G	p.Pro670Arg	missense	Exon 19 of 20	NP_001265043.1	B4DWY7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM2	ENST00000265708.9	TSL:1 MANE Select	c.2198C>G	p.Pro733Arg	missense	Exon 20 of 21	ENSP00000265708.4	Q99965-1
	ADAM2	ENST00000347580.8	TSL:1	c.2141C>G	p.Pro714Arg	missense	Exon 19 of 20	ENSP00000343854.4	Q99965-2
	ADAM2	ENST00000379853.6	TSL:1	c.1730C>G	p.Pro577Arg	missense	Exon 16 of 17	ENSP00000369182.2	Q6P2G0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244512 AF XY: 0.00000755

Gnomad AFR exome AF: 0.0000625

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: 0.00000138 AC: 2 AN: 1449568 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 721158

African (AFR) AF: 0.0000305 AC: 1 AN: 32778

American (AMR) AF: 0.00 AC: 0 AN: 43152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.00 AC: 0 AN: 39384

South Asian (SAS) AF: 0.00 AC: 0 AN: 83990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106290

Other (OTH) AF: 0.0000167 AC: 1 AN: 59756

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.51
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.022
Sift	Uncertain	0.023	D
Sift4G	Benign	0.095	T
Polyphen		0.80	P
Vest4		0.28
MVP		0.38
MPC		0.024
ClinPred		0.074	T
GERP RS		2.2
Varity_R		0.058
gMVP		0.28
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs144646998; hg19: chr8-39602389;