NM_001464.5:c.1967T>C

Variant names:

• chr8-39749359-A-G
• rs1014578269
• NM_001464.5:c.1967T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001464.5(ADAM2):​c.1967T>C​(p.Ile656Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ADAM2 NM_001464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26
• Publications: 4 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27614444).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001464.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM2	NM_001464.5	MANE Select	c.1967T>C	p.Ile656Thr	missense	Exon 18 of 21	NP_001455.3
	ADAM2	NM_001278113.2		c.1910T>C	p.Ile637Thr	missense	Exon 17 of 20	NP_001265042.1	Q99965-2
	ADAM2	NM_001278114.2		c.1778T>C	p.Ile593Thr	missense	Exon 17 of 20	NP_001265043.1	B4DWY7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM2	ENST00000265708.9	TSL:1 MANE Select	c.1967T>C	p.Ile656Thr	missense	Exon 18 of 21	ENSP00000265708.4	Q99965-1
	ADAM2	ENST00000347580.8	TSL:1	c.1910T>C	p.Ile637Thr	missense	Exon 17 of 20	ENSP00000343854.4	Q99965-2
	ADAM2	ENST00000379853.6	TSL:1	c.1499T>C	p.Ile500Thr	missense	Exon 14 of 17	ENSP00000369182.2	Q6P2G0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461236 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726930

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111560

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.0090	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.22	T
Polyphen		0.011	B
Vest4		0.36
MutPred		0.59		Loss of stability (P = 0.0187)
MVP		0.89
MPC		0.027
ClinPred		0.20	T
GERP RS		3.1
Varity_R		0.15
gMVP		0.82
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1014578269; hg19: chr8-39606878; COSMIC: COSV55864034;