8-39755767-C-A

Variant names:

• chr8-39755767-C-A
• rs1802124294
• NM_001464.5:c.1758G>T

Variant summary

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

The NM_001464.5(ADAM2):​c.1758G>T​(p.Lys586Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,336 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ADAM2 NM_001464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.83

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=0.048179507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM2	NM_001464.5	c.1758G>T	p.Lys586Asn	missense_variant	Exon 16 of 21	ENST00000265708.9	NP_001455.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM2	ENST00000265708.9	c.1758G>T	p.Lys586Asn	missense_variant	Exon 16 of 21	1	NM_001464.5	ENSP00000265708.4
ADAM2	ENST00000347580.8	c.1701G>T	p.Lys567Asn	missense_variant	Exon 15 of 20	1		ENSP00000343854.4
ADAM2	ENST00000379853.6	c.1290G>T	p.Lys430Asn	missense_variant	Exon 12 of 17	1		ENSP00000369182.2
ADAM2	ENST00000521880.5	c.1608+5414G>T		intron_variant	Intron 15 of 19	2		ENSP00000429352.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461336 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1758G>T (p.K586N) alteration is located in exon 16 (coding exon 16) of the ADAM2 gene. This alteration results from a G to T substitution at nucleotide position 1758, causing the lysine (K) at amino acid position 586 to be replaced by an asparagine (N). 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	0.26
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0060
DANN	Benign	0.60
DEOGEN2	Benign	0.046	.;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.87	N;N;N
REVEL	Benign	0.060
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.14
MutPred		0.55		.;.;Loss of ubiquitination at K586 (P = 0.0134);
MVP		0.19
MPC		0.026
ClinPred		0.045	T
GERP RS		-8.8
Varity_R		0.051
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1802124294; hg19: chr8-39613286;