chr17-4899022-T-C

Variant names:

• chr17-4899022-T-C
• rs55681486
• NM_000080.4:c.1305A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000080.4(CHRNE):​c.1305A>G​(p.Arg435Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0845 in 1,607,470 control chromosomes in the GnomAD database, including 6,198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R435R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.073 (465 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5733 hom.)
• Consequence: CHRNE NM_000080.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.847
• Publications: 11 publications found

Genes affected

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

CHRNE Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• congenital myasthenic syndrome 4A

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 4C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-4899022-T-C is Benign according to our data. Variant chr17-4899022-T-C is described in ClinVar as Benign. ClinVar VariationId is 128763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.847 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0925 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	NM_000080.4	MANE Select	c.1305A>G	p.Arg435Arg	synonymous	Exon 11 of 12	NP_000071.1	Q04844

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.1305A>G	p.Arg435Arg	synonymous	Exon 11 of 12	ENSP00000497829.1	Q04844
	CHRNE	ENST00000649830.1		c.372A>G	p.Arg124Arg	synonymous	Exon 11 of 11	ENSP00000496907.1	A0A3B3IRM1
	CHRNE	ENST00000572438.1	TSL:5	n.991A>G		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes AF: 0.0734 AC: 11156 AN: 152056 Hom.: 464 Cov.: 32

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0603

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.0608

Gnomad SAS AF: 0.0361

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0944

Gnomad OTH AF: 0.0593

GnomAD2 exomes AF: 0.0749 AC: 17689 AN: 236078 AF XY: 0.0749

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.0466

Gnomad ASJ exome AF: 0.0593

Gnomad EAS exome AF: 0.0567

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.0952

Gnomad OTH exome AF: 0.0806

GnomAD4 exome AF: 0.0857 AC: 124667 AN: 1455294 Hom.: 5733 Cov.: 36 AF XY: 0.0844 AC XY: 61027 AN XY: 723308

African (AFR) AF: 0.0279 AC: 934 AN: 33436

American (AMR) AF: 0.0476 AC: 2095 AN: 44050

Ashkenazi Jewish (ASJ) AF: 0.0594 AC: 1540 AN: 25946

East Asian (EAS) AF: 0.0805 AC: 3184 AN: 39540

South Asian (SAS) AF: 0.0305 AC: 2595 AN: 84944

European-Finnish (FIN) AF: 0.136 AC: 6997 AN: 51628

Middle Eastern (MID) AF: 0.0623 AC: 359 AN: 5758

European-Non Finnish (NFE) AF: 0.0923 AC: 102423 AN: 1109854

Other (OTH) AF: 0.0755 AC: 4540 AN: 60138

GnomAD4 genome AF: 0.0733 AC: 11155 AN: 152176 Hom.: 465 Cov.: 32 AF XY: 0.0751 AC XY: 5585 AN XY: 74396

African (AFR) AF: 0.0317 AC: 1318 AN: 41542

American (AMR) AF: 0.0602 AC: 921 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 224 AN: 3470

East Asian (EAS) AF: 0.0609 AC: 314 AN: 5152

South Asian (SAS) AF: 0.0361 AC: 174 AN: 4822

European-Finnish (FIN) AF: 0.145 AC: 1533 AN: 10588

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0944 AC: 6418 AN: 67990

Other (OTH) AF: 0.0582 AC: 123 AN: 2114

Alfa AF: 0.0832 Hom.: 186

Bravo AF: 0.0634

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Congenital myasthenic syndrome (2)
-	-	1	Congenital myasthenic syndrome 4A (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.8
DANN	Benign	0.75
PhyloP100		-0.85
PromoterAI		-0.054	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55681486; hg19: chr17-4802317; COSMIC: COSV107307942; COSMIC: COSV107307942;