8-39749674-T-C

Variant names:

• chr8-39749674-T-C
• NM_001464.5:c.1868A>G

Variant summary

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

The NM_001464.5(ADAM2):​c.1868A>G​(p.Asp623Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D623N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM2 NM_001464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.555
• 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 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	c.1868A>G	p.Asp623Gly	missense_variant	Exon 17 of 21	ENST00000265708.9	NP_001455.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM2	ENST00000265708.9	c.1868A>G	p.Asp623Gly	missense_variant	Exon 17 of 21	1	NM_001464.5	ENSP00000265708.4
ADAM2	ENST00000347580.8	c.1811A>G	p.Asp604Gly	missense_variant	Exon 16 of 20	1		ENSP00000343854.4
ADAM2	ENST00000379853.6	c.1400A>G	p.Asp467Gly	missense_variant	Exon 13 of 17	1		ENSP00000369182.2
ADAM2	ENST00000521880.5	c.1679A>G	p.Asp560Gly	missense_variant	Exon 16 of 20	2		ENSP00000429352.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1868A>G (p.D623G) alteration is located in exon 17 (coding exon 17) of the ADAM2 gene. This alteration results from a A to G substitution at nucleotide position 1868, causing the aspartic acid (D) at amino acid position 623 to be replaced by a glycine (G). 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	Benign	0.066
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.043
DANN	Benign	0.13
DEOGEN2	Benign	0.024	.;.;T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.099	T;T;T;T;.
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.043	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.91	.;.;N;.;.
PhyloP100		-0.56
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.3	N;N;N;.;N
REVEL	Benign	0.069
Sift	Benign	1.0	T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.10
MutPred		0.43		.;.;Loss of stability (P = 0.063);.;.;
MVP		0.33
MPC		0.026
ClinPred		0.055	T
GERP RS		-2.5
Varity_R		0.023
gMVP		0.67
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: -7

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

Other links and lift over

hg19: chr8-39607193;