rs149159118

Variant names:

• chr1-1046922-C-A
• rs149159118
• NM_198576.4:c.3353C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1046922-C-A
• chr1-1046922-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_198576.4(AGRN):​c.3353C>A​(p.Thr1118Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,579,524 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1118M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.50
• Publications: 10 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012785703).
• BP6: Variant 1-1046922-C-A is Benign according to our data. Variant chr1-1046922-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474116.

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.3353C>A	p.Thr1118Lys	missense	Exon 19 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.3353C>A	p.Thr1118Lys	missense	Exon 19 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.3038C>A	p.Thr1013Lys	missense	Exon 18 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.3353C>A	p.Thr1118Lys	missense	Exon 19 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.3038C>A	p.Thr1013Lys	missense	Exon 18 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.3038C>A	p.Thr1013Lys	missense	Exon 18 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152172 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00187 AC: 356 AN: 190804 AF XY: 0.00190

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.000690

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00868

Gnomad NFE exome AF: 0.00211

Gnomad OTH exome AF: 0.000800

GnomAD4 exome AF: 0.00198 AC: 2824 AN: 1427234 Hom.: 1 Cov.: 39 AF XY: 0.00192 AC XY: 1354 AN XY: 706762

African (AFR) AF: 0.000303 AC: 10 AN: 33012

American (AMR) AF: 0.000619 AC: 24 AN: 38754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.00 AC: 0 AN: 38186

South Asian (SAS) AF: 0.000466 AC: 38 AN: 81592

European-Finnish (FIN) AF: 0.00732 AC: 365 AN: 49852

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5704

European-Non Finnish (NFE) AF: 0.00210 AC: 2300 AN: 1095582

Other (OTH) AF: 0.00142 AC: 84 AN: 59134

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152290 Hom.: 1 Cov.: 33 AF XY: 0.00228 AC XY: 170 AN XY: 74456

African (AFR) AF: 0.000361 AC: 15 AN: 41566

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00203 AC: 138 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00100

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00117 AC: 140

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0030	D
Vest4		0.74
MVP		0.89
MPC		0.63
ClinPred		0.024	T
GERP RS		4.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
gMVP		0.86
Mutation Taster		=32/68	disease causing

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: rs149159118; hg19: chr1-982302;