chr1-1045973-C-T

Variant names:

• chr1-1045973-C-T
• rs116836855
• NM_198576.4:c.2690C>T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:6
• Conservation: PhyloP100: 0.295
• Publications: 3 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: STRONG Submitted by: PanelApp Australia, 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 -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 VariationId is 235570.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 1939 alleles in the male GnomAdExome4 subpopulation. Median coverage is 39. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.2690C>T	p.Ala897Val	missense	Exon 16 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.2690C>T	p.Ala897Val	missense	Exon 16 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.2375C>T	p.Ala792Val	missense	Exon 15 of 36	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.2690C>T	p.Ala897Val	missense	Exon 16 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.2375C>T	p.Ala792Val	missense	Exon 15 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.2375C>T	p.Ala792Val	missense	Exon 15 of 35	ENSP00000498543.1

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

GnomAD2 exomes AF: 0.00197 AC: 493 AN: 250082 AF XY: 0.00197

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 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

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.00179 AC: 80 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.000925 AC: 49 AN: 52974

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00331 AC: 3686 AN: 1112000

Other (OTH) AF: 0.00171 AC: 103 AN: 60386

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

African (AFR) AF: 0.000313 AC: 13 AN: 41566

American (AMR) AF: 0.00314 AC: 48 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00340 AC: 231 AN: 68008

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

Alfa AF: 0.00240 Hom.: 1

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	1	AGRN-related disorder (1)
-	-	1	Congenital myasthenic syndrome 8 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
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
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.29
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Benign	0.30	T
Sift4G	Benign	0.10	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs116836855; hg19: chr1-981353; COSMIC: COSV108905479; COSMIC: COSV108905479;