rs2229199

Variant names:

• chr17-4898699-C-T
• rs2229199
• NM_000080.4:c.*37G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000080.4(CHRNE):​c.*37G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00806 in 1,595,984 control chromosomes in the GnomAD database, including 458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (218 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (240 hom.)
• Consequence: CHRNE NM_000080.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.263
• Publications: 1 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-4898699-C-T is Benign according to our data. Variant chr17-4898699-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	NM_000080.4	MANE Select	c.*37G>A		3_prime_UTR	Exon 12 of 12	NP_000071.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.*37G>A		3_prime_UTR	Exon 12 of 12	ENSP00000497829.1
	CHRNE	ENST00000572438.1	TSL:5	n.1205G>A		non_coding_transcript_exon	Exon 7 of 7
	CHRNE	ENST00000652550.1		n.1245G>A		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4961 AN: 152074 Hom.: 218 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00249

Gnomad OTH AF: 0.0326

GnomAD2 exomes AF: 0.0106 AC: 2347 AN: 221358 AF XY: 0.00860

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.00547 AC: 7893 AN: 1443792 Hom.: 240 Cov.: 33 AF XY: 0.00503 AC XY: 3605 AN XY: 716336

African (AFR) AF: 0.112 AC: 3735 AN: 33368

American (AMR) AF: 0.0120 AC: 492 AN: 41120

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 590 AN: 25638

East Asian (EAS) AF: 0.00 AC: 0 AN: 39142

South Asian (SAS) AF: 0.000456 AC: 38 AN: 83344

European-Finnish (FIN) AF: 0.0000780 AC: 4 AN: 51302

Middle Eastern (MID) AF: 0.0176 AC: 101 AN: 5732

European-Non Finnish (NFE) AF: 0.00198 AC: 2189 AN: 1104310

Other (OTH) AF: 0.0124 AC: 744 AN: 59836

GnomAD4 genome AF: 0.0326 AC: 4969 AN: 152192 Hom.: 218 Cov.: 33 AF XY: 0.0314 AC XY: 2340 AN XY: 74410

African (AFR) AF: 0.105 AC: 4356 AN: 41522

American (AMR) AF: 0.0186 AC: 284 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3468

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00249 AC: 169 AN: 67992

Other (OTH) AF: 0.0323 AC: 68 AN: 2106

Alfa AF: 0.0186 Hom.: 35

Bravo AF: 0.0374

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.9
DANN	Benign	0.62
PhyloP100		-0.26
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: rs2229199; hg19: chr17-4801994;