rs142416636

Variant names:

• chr1-1047342-A-G
• rs142416636
• NM_198576.4:c.3404A>G

Variant summary

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

The NM_198576.4(AGRN):​c.3404A>G​(p.Gln1135Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00958 in 1,605,086 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (26 hom., cov: 34)
  • Exomes 𝑓: 0.0098 (255 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.00
• Publications: 12 publications found

Genes affected

AGRN (HGNC:329): (agrin) This gene encodes one of several proteins that are critical in the development of the neuromuscular junction (NMJ), as identified in mouse knock-out studies. The encoded protein contains several laminin G, Kazal type serine protease inhibitor, and epidermal growth factor domains. Additional post-translational modifications occur to add glycosaminoglycans and disulfide bonds. In one family with congenital myasthenic syndrome affecting limb-girdle muscles, a mutation in this gene was found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

AGRN Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 8

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.007086724).
• BP6: Variant 1-1047342-A-G is Benign according to our data. Variant chr1-1047342-A-G is described in ClinVar as Benign. ClinVar VariationId is 128299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. 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
	AGRN	NM_198576.4	MANE Select	c.3404A>G	p.Gln1135Arg	missense	Exon 20 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.3404A>G	p.Gln1135Arg	missense	Exon 20 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.3089A>G	p.Gln1030Arg	missense	Exon 19 of 36	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.3404A>G	p.Gln1135Arg	missense	Exon 20 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.3089A>G	p.Gln1030Arg	missense	Exon 19 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.3089A>G	p.Gln1030Arg	missense	Exon 19 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1180 AN: 152210 Hom.: 26 Cov.: 34

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.0573

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00866

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0130 AC: 3174 AN: 243754 AF XY: 0.0159

Gnomad AFR exome AF: 0.00193

Gnomad AMR exome AF: 0.00294

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.00395

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.00819

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.00977 AC: 14198 AN: 1452758 Hom.: 255 Cov.: 32 AF XY: 0.0115 AC XY: 8280 AN XY: 722106

African (AFR) AF: 0.00127 AC: 42 AN: 33122

American (AMR) AF: 0.00299 AC: 129 AN: 43168

Ashkenazi Jewish (ASJ) AF: 0.0299 AC: 770 AN: 25716

East Asian (EAS) AF: 0.00179 AC: 71 AN: 39608

South Asian (SAS) AF: 0.0567 AC: 4824 AN: 85048

European-Finnish (FIN) AF: 0.00439 AC: 229 AN: 52160

Middle Eastern (MID) AF: 0.0307 AC: 176 AN: 5730

European-Non Finnish (NFE) AF: 0.00648 AC: 7187 AN: 1108284

Other (OTH) AF: 0.0129 AC: 770 AN: 59922

GnomAD4 genome AF: 0.00773 AC: 1177 AN: 152328 Hom.: 26 Cov.: 34 AF XY: 0.00839 AC XY: 625 AN XY: 74488

African (AFR) AF: 0.00125 AC: 52 AN: 41590

American (AMR) AF: 0.00418 AC: 64 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 100 AN: 3472

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5178

South Asian (SAS) AF: 0.0574 AC: 277 AN: 4826

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00866 AC: 589 AN: 68006

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00857 Hom.: 22

Bravo AF: 0.00612

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.0140 AC: 1697

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.0102

EpiControl AF: 0.00765

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.19
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0070	D
Vest4		0.52
MPC		0.59
ClinPred		0.013	T
GERP RS		4.2
gMVP		0.68
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs142416636; hg19: chr1-982722; COSMIC: COSV106113326; COSMIC: COSV106113326;