8-39761261-C-G

Variant names:

• chr8-39761261-C-G
• NM_001464.5:c.1528G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001464.5(ADAM2):​c.1528G>C​(p.Glu510Gln) 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. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAM2 NM_001464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.212

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

Verdict is Uncertain_significance. Variant got 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.1528G>C	p.Glu510Gln	missense_variant	Exon 15 of 21	ENST00000265708.9	NP_001455.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM2	ENST00000265708.9	c.1528G>C	p.Glu510Gln	missense_variant	Exon 15 of 21	1	NM_001464.5	ENSP00000265708.4
ADAM2	ENST00000347580.8	c.1471G>C	p.Glu491Gln	missense_variant	Exon 14 of 20	1		ENSP00000343854.4
ADAM2	ENST00000379853.6	c.1150G>C	p.Glu384Gln	missense_variant	Exon 11 of 17	1		ENSP00000369182.2
ADAM2	ENST00000521880.5	c.1528G>C	p.Glu510Gln	missense_variant	Exon 15 of 20	2		ENSP00000429352.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1528G>C (p.E510Q) alteration is located in exon 15 (coding exon 15) of the ADAM2 gene. This alteration results from a G to C substitution at nucleotide position 1528, causing the glutamic acid (E) at amino acid position 510 to be replaced by a glutamine (Q). 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	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.0
DANN	Benign	0.96
DEOGEN2	Benign	0.026	.;.;T;T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.66	T;T;T;T;.
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.42	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;.;L;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.0	N;N;N;.;N
REVEL	Benign	0.034
Sift	Benign	0.15	T;T;T;.;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.28	B;B;B;B;B
Vest4		0.35
MutPred		0.51		.;.;Loss of disorder (P = 0.1149);Loss of disorder (P = 0.1149);Loss of disorder (P = 0.1149);
MVP		0.37
MPC		0.027
ClinPred		0.14	T
GERP RS		1.4
Varity_R		0.13
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: 20

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-39618780;