rs116836855

chr1-1045973-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198576.4(AGRN):c.2690C>T(p.Ala897Val) 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 1,613,700 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A897A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (7 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.295

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008817881).
• BP6: Variant 1-1045973-C-T is Benign according to our data. Variant chr1-1045973-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235570.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00269 (3934/1461404) while in subpopulation NFE AF= 0.00331 (3686/1112000). AF 95% confidence interval is 0.00323. There are 7 homozygotes in gnomad4_exome. There are 1939 alleles in male gnomad4_exome subpopulation. Median coverage is 39. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.2690C>T	p.Ala897Val	missense_variant	16/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.2690C>T	p.Ala897Val	missense_variant	16/36	1	NM_198576.4	P1

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00197 AC: 493 AN: 250082 Hom.: 2 AF XY: 0.00197 AC XY: 267 AN XY: 135500

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.000559

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00269 AC: 3934 AN: 1461404 Hom.: 7 Cov.: 39 AF XY: 0.00267 AC XY: 1939 AN XY: 727008

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000925

Gnomad4 NFE exome AF: 0.00331

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.00181 AC XY: 135 AN XY: 74466

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00340

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00227 Hom.: 0

Bravo AF: 0.00181

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00208 AC: 252

EpiCase AF: 0.00289

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

The c.2690C>T (p.A897V) alteration is located in exon 16 (coding exon 16) of the AGRN gene. This alteration results from a C to T substitution at nucleotide position 2690, causing the alanine (A) at amino acid position 897 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 18, 2020

- -

AGRN-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital myasthenic syndrome 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	10
Dann	Uncertain	0.98
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.18
Sift	Benign	0.30	T;.
Sift4G	Benign	0.10	T;T
Vest4		0.090
MVP		0.79
MPC		0.45
ClinPred		0.028	T
GERP RS		2.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs116836855; hg19: chr1-981353;