2-206445446-A-G

Position:

• chr2-206445446-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000264377.8(ADAM23):​c.354A>G​(p.Ile118Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,614,192 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I118T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (10 hom.)
• Consequence: ADAM23 ENST00000264377.8 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.292

Genes affected

ADAM23 (HGNC:202): (ADAM metallopeptidase domain 23) 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. It is reported that inactivation of this gene is associated with tumorigenesis in human cancers. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011896282).
• BP6: Variant 2-206445446-A-G is Benign according to our data. Variant chr2-206445446-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 787583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 270 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM23	NM_003812.4	c.354A>G	p.Ile118Met	missense_variant	2/26	ENST00000264377.8	NP_003803.1
ADAM23	NM_001410985.1	c.354A>G	p.Ile118Met	missense_variant	2/26		NP_001397914.1
ADAM23	XM_005246932.4	c.354A>G	p.Ile118Met	missense_variant	2/25		XP_005246989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM23	ENST00000264377.8	c.354A>G	p.Ile118Met	missense_variant	2/26	1	NM_003812.4	ENSP00000264377	P4
ADAM23	ENST00000374415.7	c.354A>G	p.Ile118Met	missense_variant	2/26	5		ENSP00000363536	A1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00204 AC: 513 AN: 251360 Hom.: 1 AF XY: 0.00208 AC XY: 283 AN XY: 135856

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00271 AC: 3962 AN: 1461836 Hom.: 10 Cov.: 31 AF XY: 0.00272 AC XY: 1977 AN XY: 727218

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00206

Gnomad4 FIN exome AF: 0.000655

Gnomad4 NFE exome AF: 0.00314

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00177 AC: 270 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74500

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00272

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00248 Hom.: 0

Bravo AF: 0.00174

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00320

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.73	P;.
Vest4		0.32
MVP		0.15
MPC		0.24
ClinPred		0.065	T
GERP RS		-6.7
Varity_R		0.11
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs146724325; hg19: chr2-207310170;