7-87935182-C-G

Variant names:

• chr7-87935182-C-G
• rs2279542
• NM_001324418.2:c.242C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001324418.2(ADAM22):​c.242C>G​(p.Pro81Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,600,082 control chromosomes in the GnomAD database, including 230,061 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P81A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.63 (32682 hom., cov: 30)
  • Exomes 𝑓: 0.52 (197379 hom.)
• Consequence: ADAM22 NM_001324418.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.991
• Publications: 32 publications found

Genes affected

ADAM22 (HGNC:201): (ADAM metallopeptidase domain 22) 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. Unlike other members of the ADAM protein family, the protein encoded by this gene lacks metalloprotease activity since it has no zinc-binding motif. This gene is highly expressed in the brain and may function as an integrin ligand in the brain. In mice, it has been shown to be essential for correct myelination in the peripheral nervous system. Alternative splicing results in several transcript variants.[provided by RefSeq, Dec 2010]

ADAM22 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 61

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.7454687E-7).
• BP6: Variant 7-87935182-C-G is Benign according to our data. Variant chr7-87935182-C-G is described in ClinVar as Benign. ClinVar VariationId is 1188945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324418.2. 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
	ADAM22	NM_001324418.2	MANE Select	c.242C>G	p.Pro81Arg	missense	Exon 2 of 32	NP_001311347.1	H7C3I4
	ADAM22	NM_001324419.2		c.239C>G	p.Pro80Arg	missense	Exon 2 of 32	NP_001311348.1
	ADAM22	NM_001391975.1		c.242C>G	p.Pro81Arg	missense	Exon 2 of 33	NP_001378904.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM22	ENST00000413139.2	TSL:5 MANE Select	c.242C>G	p.Pro81Arg	missense	Exon 2 of 32	ENSP00000412085.2	H7C3I4
	ADAM22	ENST00000265727.11	TSL:1	c.242C>G	p.Pro81Arg	missense	Exon 2 of 31	ENSP00000265727.7	Q9P0K1-1
	ADAM22	ENST00000398209.7	TSL:1	c.242C>G	p.Pro81Arg	missense	Exon 2 of 31	ENSP00000381267.3	Q9P0K1-2

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95658 AN: 151782 Hom.: 32609 Cov.: 30

Gnomad AFR AF: 0.912

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.634

GnomAD2 exomes AF: 0.537 AC: 118346 AN: 220508 AF XY: 0.523

Gnomad AFR exome AF: 0.922

Gnomad AMR exome AF: 0.561

Gnomad ASJ exome AF: 0.569

Gnomad EAS exome AF: 0.551

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.516 AC: 747885 AN: 1448182 Hom.: 197379 Cov.: 54 AF XY: 0.510 AC XY: 367020 AN XY: 719120

African (AFR) AF: 0.927 AC: 30876 AN: 33290

American (AMR) AF: 0.561 AC: 24173 AN: 43060

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 14620 AN: 25644

East Asian (EAS) AF: 0.546 AC: 21564 AN: 39478

South Asian (SAS) AF: 0.366 AC: 31104 AN: 85046

European-Finnish (FIN) AF: 0.536 AC: 27618 AN: 51518

Middle Eastern (MID) AF: 0.534 AC: 2985 AN: 5590

European-Non Finnish (NFE) AF: 0.510 AC: 563044 AN: 1104790

Other (OTH) AF: 0.534 AC: 31901 AN: 59766

GnomAD4 genome AF: 0.631 AC: 95797 AN: 151900 Hom.: 32682 Cov.: 30 AF XY: 0.626 AC XY: 46439 AN XY: 74228

African (AFR) AF: 0.912 AC: 37841 AN: 41498

American (AMR) AF: 0.595 AC: 9093 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1983 AN: 3470

East Asian (EAS) AF: 0.540 AC: 2758 AN: 5104

South Asian (SAS) AF: 0.370 AC: 1777 AN: 4806

European-Finnish (FIN) AF: 0.532 AC: 5610 AN: 10536

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.512 AC: 34768 AN: 67896

Other (OTH) AF: 0.633 AC: 1334 AN: 2108

Alfa AF: 0.493 Hom.: 2674

Bravo AF: 0.649

TwinsUK AF: 0.502 AC: 1862

ALSPAC AF: 0.506 AC: 1952

ESP6500AA AF: 0.892 AC: 3375

ESP6500EA AF: 0.516 AC: 4227

ExAC AF: 0.527 AC: 62567

Asia WGS AF: 0.487 AC: 1699 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 61 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.84
DANN	Benign	0.79
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.012	T
MetaRNN	Benign	6.7e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.99
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.020
Sift	Benign	0.67	T
Sift4G	Benign	0.70	T
Polyphen		0.0010	B
Vest4		0.032
MPC		0.53
ClinPred		0.0023	T
GERP RS		-5.3
PromoterAI		-0.027	Neutral
Varity_R		0.049
gMVP		0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2279542; hg19: chr7-87564497; COSMIC: COSV55969663;