rs139415524

Positions:

• chr1-1051811-G-A
• chr1-1051811-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_198576.4(AGRN):​c.5647G>A​(p.Glu1883Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,613,624 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.75

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010705084).
• BP6: Variant 1-1051811-G-A is Benign according to our data. Variant chr1-1051811-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00159 (242/152310) while in subpopulation AFR AF= 0.00534 (222/41566). AF 95% confidence interval is 0.00476. There are 1 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5647G>A	p.Glu1883Lys	missense_variant	33/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5647G>A	p.Glu1883Lys	missense_variant	33/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.5344G>A	p.Glu1782Lys	missense_variant	33/38			ENSP00000499046
AGRN	ENST00000652369.1	c.5332G>A	p.Glu1778Lys	missense_variant	32/35			ENSP00000498543
AGRN	ENST00000620552.4	c.5245G>A	p.Glu1749Lys	missense_variant	34/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 241 AN: 152192 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000471 AC: 118 AN: 250302 Hom.: 0 AF XY: 0.000339 AC XY: 46 AN XY: 135702

Gnomad AFR exome AF: 0.00557

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000195 AC: 285 AN: 1461314 Hom.: 0 Cov.: 84 AF XY: 0.000166 AC XY: 121 AN XY: 726962

Gnomad4 AFR exome AF: 0.00547

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152310 Hom.: 1 Cov.: 34 AF XY: 0.00146 AC XY: 109 AN XY: 74464

Gnomad4 AFR AF: 0.00534

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000865 Hom.: 1

Bravo AF: 0.00175

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital myasthenic syndrome 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.89
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.0072
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.92	D;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.030	N;.
REVEL	Benign	0.26
Sift	Benign	0.91	T;.
Sift4G	Benign	0.87	T;T
Vest4		0.40
MVP		0.83
MPC		0.16
ClinPred		0.012	T
GERP RS		2.9
gMVP		0.42

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: rs139415524; hg19: chr1-987191; COSMIC: COSV65072111; COSMIC: COSV65072111;