rs144646998

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr8-39744870-G-T
• chr8-39744870-G-A
• chr8-39744870-G-C

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>A​(p.Pro733His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,449,570 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ADAM2 NM_001464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.13942808).

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>A	p.Pro733His	missense	Exon 20 of 21	NP_001455.3
	ADAM2	NM_001278113.2		c.2141C>A	p.Pro714His	missense	Exon 19 of 20	NP_001265042.1	Q99965-2
	ADAM2	NM_001278114.2		c.2009C>A	p.Pro670His	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>A	p.Pro733His	missense	Exon 20 of 21	ENSP00000265708.4	Q99965-1
	ADAM2	ENST00000347580.8	TSL:1	c.2141C>A	p.Pro714His	missense	Exon 19 of 20	ENSP00000343854.4	Q99965-2
	ADAM2	ENST00000379853.6	TSL:1	c.1730C>A	p.Pro577His	missense	Exon 16 of 17	ENSP00000369182.2	Q6P2G0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000818 AC: 2 AN: 244512 AF XY: 0.00000755

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000604

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: 0.00000276 AC: 4 AN: 1449570 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 721160

African (AFR) AF: 0.00 AC: 0 AN: 32780

American (AMR) AF: 0.0000927 AC: 4 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: 0.00 AC: 0 AN: 59756

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.82
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.51
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.048
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.038	D
Polyphen		0.92	P
Vest4		0.28
MutPred		0.29		Loss of glycosylation at P733 (P = 0.0453)
MVP		0.38
MPC		0.025
ClinPred		0.22	T
GERP RS		2.2
Varity_R		0.11
gMVP		0.25
Mutation Taster		=96/4	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;