8-39746580-A-G

Variant names:

• chr8-39746580-A-G
• NM_001464.5:c.2066T>C

Variant summary

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

The NM_001464.5(ADAM2):​c.2066T>C​(p.Phe689Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 1.19

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.2066T>C	p.Phe689Ser	missense_variant	Exon 19 of 21	ENST00000265708.9	NP_001455.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM2	ENST00000265708.9	c.2066T>C	p.Phe689Ser	missense_variant	Exon 19 of 21	1	NM_001464.5	ENSP00000265708.4
ADAM2	ENST00000347580.8	c.2009T>C	p.Phe670Ser	missense_variant	Exon 18 of 20	1		ENSP00000343854.4
ADAM2	ENST00000379853.6	c.1598T>C	p.Phe533Ser	missense_variant	Exon 15 of 17	1		ENSP00000369182.2
ADAM2	ENST00000521880.5	c.1877T>C	p.Phe626Ser	missense_variant	Exon 18 of 20	2		ENSP00000429352.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2066T>C (p.F689S) alteration is located in exon 19 (coding exon 19) of the ADAM2 gene. This alteration results from a T to C substitution at nucleotide position 2066, causing the phenylalanine (F) at amino acid position 689 to be replaced by a serine (S). 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	0.24
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;.;T;T;T
Eigen	Benign	-0.063
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.69	T;T;T;T;.
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.70	D;D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.3	.;.;L;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.4	D;D;D;.;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.088	B;P;B;P;P
Vest4		0.67
MutPred		0.40		.;.;Loss of stability (P = 0.0953);.;.;
MVP		0.97
MPC		0.17
ClinPred		0.93	D
GERP RS		3.6
Varity_R		0.31
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: chr8-39604099;