chr1-1041976-C-T

Position:

• chr1-1041976-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_198576.4(AGRN):​c.1198C>T​(p.Arg400Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,611,772 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict 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. R400Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00019 (3 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.489

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01354447).
• BP6: Variant 1-1041976-C-T is Benign according to our data. Variant chr1-1041976-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474098.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.1198C>T	p.Arg400Trp	missense_variant	7/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.1198C>T	p.Arg400Trp	missense_variant	7/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.883C>T	p.Arg295Trp	missense_variant	6/38
AGRN	ENST00000652369.1	c.883C>T	p.Arg295Trp	missense_variant	6/35
AGRN	ENST00000620552.4	c.784C>T	p.Arg262Trp	missense_variant	7/39	5

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152160 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000318 AC: 78 AN: 245578 Hom.: 0 AF XY: 0.000276 AC XY: 37 AN XY: 133964

Gnomad AFR exome AF: 0.00305

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000186 AC: 271 AN: 1459494 Hom.: 3 Cov.: 77 AF XY: 0.000185 AC XY: 134 AN XY: 726134

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152278 Hom.: 0 Cov.: 34 AF XY: 0.000860 AC XY: 64 AN XY: 74460

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000222 Hom.: 0

Bravo AF: 0.00106

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000454 AC: 55

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 8 Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jul 04, 2017	The observed variant c.1198C>T (p.Arg400Trp) has a minor allele frequency of 0.0016 and 0.0005 in 1000 Genomes and ExAC databases respectively. The in silico prediction of the variant is benign by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 01, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 30, 2024

Variant summary: AGRN c.1198C>T (p.Arg400Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 1610860 control chromosomes in the gnomAD database (v4.1 dataset), including 3 homozygotes. The variant was found predominantly within the African or African-American subpopulation at a frequency of 0.003. The observed variant frequency within African or African-American control individuals, together with the presence in homozygotes suggest that the variant might be benign. To our knowledge, no occurrence of c.1198C>T in individuals affected with Congenital Myasthenic Syndrome-8 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 474098). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.11	N
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Benign	0.25
Sift	Uncertain	0.013	D;.
Sift4G	Uncertain	0.0030	D;D
Vest4		0.22
MVP		0.84
MPC		0.49
ClinPred		0.024	T
GERP RS		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
gMVP		0.28

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: rs149636063; hg19: chr1-977356; COSMIC: COSV65069633; COSMIC: COSV65069633;