8-39749692-G-A

Variant names:

• chr8-39749692-G-A
• NM_001464.5:c.1850C>T

Variant summary

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

The NM_001464.5(ADAM2):​c.1850C>T​(p.Thr617Ile) 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. 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: 0.720

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.1850C>T	p.Thr617Ile	missense_variant	Exon 17 of 21	ENST00000265708.9	NP_001455.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM2	ENST00000265708.9	c.1850C>T	p.Thr617Ile	missense_variant	Exon 17 of 21	1	NM_001464.5	ENSP00000265708.4
ADAM2	ENST00000347580.8	c.1793C>T	p.Thr598Ile	missense_variant	Exon 16 of 20	1		ENSP00000343854.4
ADAM2	ENST00000379853.6	c.1382C>T	p.Thr461Ile	missense_variant	Exon 13 of 17	1		ENSP00000369182.2
ADAM2	ENST00000521880.5	c.1661C>T	p.Thr554Ile	missense_variant	Exon 16 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 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1850C>T (p.T617I) alteration is located in exon 17 (coding exon 17) of the ADAM2 gene. This alteration results from a C to T substitution at nucleotide position 1850, causing the threonine (T) at amino acid position 617 to be replaced by an isoleucine (I). 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	0.20
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.0
DANN	Benign	0.97
DEOGEN2	Benign	0.21	.;.;T;T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.67	T;T;T;T;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.0	.;.;M;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D;D;D;.;D
REVEL	Benign	0.052
Sift	Benign	0.14	T;D;T;.;T
Sift4G	Uncertain	0.054	T;D;T;T;T
Polyphen		0.39	B;B;B;B;B
Vest4		0.31
MutPred		0.41		.;.;Loss of disorder (P = 0.0351);.;.;
MVP		0.88
MPC		0.028
ClinPred		0.25	T
GERP RS		1.0
Varity_R		0.088
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: -25

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: chr8-39607211;