8-39766885-C-T

Variant names:

• chr8-39766885-C-T
• rs761554819
• NM_001464.5:c.1470G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001464.5(ADAM2):​c.1470G>A​(p.Met490Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,611,342 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ADAM2 NM_001464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.322
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059422553).

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.1470G>A	p.Met490Ile	missense	Exon 14 of 21	NP_001455.3
	ADAM2	NM_001278113.2		c.1413G>A	p.Met471Ile	missense	Exon 13 of 20	NP_001265042.1	Q99965-2
	ADAM2	NM_001278114.2		c.1470G>A	p.Met490Ile	missense	Exon 14 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.1470G>A	p.Met490Ile	missense	Exon 14 of 21	ENSP00000265708.4	Q99965-1
	ADAM2	ENST00000347580.8	TSL:1	c.1413G>A	p.Met471Ile	missense	Exon 13 of 20	ENSP00000343854.4	Q99965-2
	ADAM2	ENST00000379853.6	TSL:1	c.1092G>A	p.Met364Ile	missense	Exon 10 of 17	ENSP00000369182.2	Q6P2G0

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250538 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00000411 AC: 6 AN: 1459166 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725334

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.0000672 AC: 3 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 86014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110072

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

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	0.16
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.22
DANN	Benign	0.61
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.050	N
PhyloP100		-0.32
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.041
Sift	Benign	0.28	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.55		Loss of methylation at K494 (P = 0.1042)
MVP		0.11
MPC		0.025
ClinPred		0.024	T
GERP RS		-6.3
Varity_R		0.081
gMVP		0.65
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761554819; hg19: chr8-39624404;