8-39761227-A-C

Variant names:

• chr8-39761227-A-C
• NM_001464.5:c.1562T>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001464.5(ADAM2):​c.1562T>G​(p.Val521Gly) 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. 15/21 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)
• Consequence: ADAM2 NM_001464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.36

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051108897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM2	NM_001464.5	c.1562T>G	p.Val521Gly	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.1562T>G	p.Val521Gly	missense_variant	Exon 15 of 21	1	NM_001464.5	ENSP00000265708.4
ADAM2	ENST00000347580.8	c.1505T>G	p.Val502Gly	missense_variant	Exon 14 of 20	1		ENSP00000343854.4
ADAM2	ENST00000379853.6	c.1184T>G	p.Val395Gly	missense_variant	Exon 11 of 17	1		ENSP00000369182.2
ADAM2	ENST00000521880.5	c.1562T>G	p.Val521Gly	missense_variant	Exon 15 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

Nov 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1562T>G (p.V521G) alteration is located in exon 15 (coding exon 15) of the ADAM2 gene. This alteration results from a T to G substitution at nucleotide position 1562, causing the valine (V) at amino acid position 521 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	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.090
DANN	Benign	0.46
DEOGEN2	Benign	0.055	.;.;T;T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.46	T;T;T;T;.
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.051	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;L;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.5	N;N;N;.;N
REVEL	Benign	0.022
Sift	Benign	0.38	T;T;T;.;T
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.051	B;B;B;B;B
Vest4		0.21
MutPred		0.43		.;.;Gain of disorder (P = 0.026);Gain of disorder (P = 0.026);Gain of disorder (P = 0.026);
MVP		0.13
MPC		0.027
ClinPred		0.24	T
GERP RS		-9.0
Varity_R		0.13
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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: chr8-39618746;