rs201499441

Variant names:

• chr8-39746506-T-C
• rs201499441
• NM_001464.5:c.2140A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001464.5(ADAM2):​c.2140A>G​(p.Lys714Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,596,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: ADAM2 NM_001464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08398822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM2	NM_001464.5	c.2140A>G	p.Lys714Glu	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.2140A>G	p.Lys714Glu	missense_variant	Exon 19 of 21	1	NM_001464.5	ENSP00000265708.4
ADAM2	ENST00000347580.8	c.2083A>G	p.Lys695Glu	missense_variant	Exon 18 of 20	1		ENSP00000343854.4
ADAM2	ENST00000379853.6	c.1672A>G	p.Lys558Glu	missense_variant	Exon 15 of 17	1		ENSP00000369182.2
ADAM2	ENST00000521880.5	c.1951A>G	p.Lys651Glu	missense_variant	Exon 18 of 20	2		ENSP00000429352.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000123 AC: 29 AN: 236272 AF XY: 0.000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000931

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000105 AC: 151 AN: 1444294 Hom.: 0 Cov.: 28 AF XY: 0.000111 AC XY: 80 AN XY: 718196

African (AFR) AF: 0.00 AC: 0 AN: 32334

American (AMR) AF: 0.00 AC: 0 AN: 40890

Ashkenazi Jewish (ASJ) AF: 0.00120 AC: 31 AN: 25750

East Asian (EAS) AF: 0.00 AC: 0 AN: 39054

South Asian (SAS) AF: 0.000232 AC: 19 AN: 81964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.0000823 AC: 91 AN: 1105822

Other (OTH) AF: 0.000167 AC: 10 AN: 59728

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74342

African (AFR) AF: 0.0000482 AC: 2 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2140A>G (p.K714E) alteration is located in exon 19 (coding exon 19) of the ADAM2 gene. This alteration results from a A to G substitution at nucleotide position 2140, causing the lysine (K) at amino acid position 714 to be replaced by a glutamic acid (E). 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	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	.;.;T;T;T
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.59	T;T;T;T;.
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.084	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;.;L;.;.
PhyloP100		1.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	N;D;N;.;N
REVEL	Benign	0.075
Sift	Uncertain	0.011	D;D;D;.;D
Sift4G	Uncertain	0.024	D;D;D;D;D
Polyphen		1.0	D;P;D;D;D
Vest4		0.29
MVP		0.32
MPC		0.032
ClinPred		0.13	T
GERP RS		3.9
Varity_R		0.28
gMVP		0.31
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs201499441; hg19: chr8-39604025;