chr1-1043223-CCT-C

Variant names:

• chr1-1043223-CCT-C
• rs35881187
• NM_198576.4:c.1385-15_1385-14delCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_198576.4(AGRN):​c.1385-15_1385-14delCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,587,886 control chromosomes in the GnomAD database, including 243,783 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (18390 hom., cov: 0)
  • Exomes 𝑓: 0.55 (225393 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.112
• 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 -16 ACMG points.

• BP6: Variant 1-1043223-CCT-C is Benign according to our data. Variant chr1-1043223-CCT-C is described in ClinVar as Benign. ClinVar VariationId is 263160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.1385-15_1385-14delCT		intron_variant	Intron 7 of 35	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.1385-15_1385-14delCT		intron_variant	Intron 7 of 35	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.1070-15_1070-14delCT		intron_variant	Intron 6 of 37			ENSP00000499046.1
AGRN	ENST00000652369.2	c.1070-15_1070-14delCT		intron_variant	Intron 6 of 34			ENSP00000498543.1
AGRN	ENST00000620552.4	c.971-15_971-14delCT		intron_variant	Intron 7 of 38	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67234 AN: 151712 Hom.: 18381 Cov.: 0

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.477

GnomAD2 exomes AF: 0.551 AC: 113916 AN: 206582 AF XY: 0.552

Gnomad AFR exome AF: 0.0943

Gnomad AMR exome AF: 0.697

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.786

Gnomad FIN exome AF: 0.535

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.539

GnomAD4 exome AF: 0.553 AC: 794283 AN: 1436056 Hom.: 225393 AF XY: 0.553 AC XY: 393599 AN XY: 711874

African (AFR) AF: 0.0899 AC: 2995 AN: 33302

American (AMR) AF: 0.684 AC: 27063 AN: 39554

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 14014 AN: 25544

East Asian (EAS) AF: 0.802 AC: 30952 AN: 38600

South Asian (SAS) AF: 0.549 AC: 45177 AN: 82250

European-Finnish (FIN) AF: 0.539 AC: 27116 AN: 50332

Middle Eastern (MID) AF: 0.501 AC: 2863 AN: 5716

European-Non Finnish (NFE) AF: 0.556 AC: 612368 AN: 1101182

Other (OTH) AF: 0.533 AC: 31735 AN: 59576

GnomAD4 genome AF: 0.443 AC: 67250 AN: 151830 Hom.: 18390 Cov.: 0 AF XY: 0.449 AC XY: 33341 AN XY: 74198

African (AFR) AF: 0.110 AC: 4546 AN: 41484

American (AMR) AF: 0.623 AC: 9504 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1932 AN: 3466

East Asian (EAS) AF: 0.786 AC: 4041 AN: 5144

South Asian (SAS) AF: 0.554 AC: 2668 AN: 4812

European-Finnish (FIN) AF: 0.537 AC: 5655 AN: 10540

Middle Eastern (MID) AF: 0.503 AC: 146 AN: 290

European-Non Finnish (NFE) AF: 0.549 AC: 37199 AN: 67814

Other (OTH) AF: 0.482 AC: 1016 AN: 2106

Alfa AF: 0.504 Hom.: 3738

Bravo AF: 0.436

Asia WGS AF: 0.647 AC: 2252 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 8 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 27, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs35881187; hg19: chr1-978603;