NM_000080.4:c.*43T>C

Variant names:

• chr17-4898693-A-G
• rs2229200
• NM_000080.4:c.*43T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000080.4(CHRNE):​c.*43T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00812 in 1,589,882 control chromosomes in the GnomAD database, including 459 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 (219 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: -3.92

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 17-4898693-A-G is Benign according to our data. Variant chr17-4898693-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 254885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4898693-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.*43T>C		3_prime_UTR_variant	Exon 12 of 12	ENST00000649488.2	NP_000071.1
CHRNE	XM_017024115.2	c.*43T>C		3_prime_UTR_variant	Exon 13 of 13		XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488	c.*43T>C		3_prime_UTR_variant	Exon 12 of 12		NM_000080.4	ENSP00000497829.1
CHRNE	ENST00000649830	c.*161T>C		3_prime_UTR_variant	Exon 11 of 11			ENSP00000496907.1
CHRNE	ENST00000572438.1	n.1211T>C		non_coding_transcript_exon_variant	Exon 7 of 7	5
CHRNE	ENST00000652550.1	n.1251T>C		non_coding_transcript_exon_variant	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4975 AN: 152024 Hom.: 219 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0107 AC: 2273 AN: 212434 Hom.: 79 AF XY: 0.00878 AC XY: 1003 AN XY: 114258

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00266

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.00551 AC: 7928 AN: 1437740 Hom.: 240 Cov.: 33 AF XY: 0.00509 AC XY: 3629 AN XY: 712758

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.0231

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000460

Gnomad4 FIN exome AF: 0.0000789

Gnomad4 NFE exome AF: 0.00202

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0328 AC: 4983 AN: 152142 Hom.: 219 Cov.: 33 AF XY: 0.0316 AC XY: 2350 AN XY: 74376

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0187

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00255

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.00719 Hom.: 7

Bravo AF: 0.0374

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital myasthenic syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.14
DANN	Benign	0.24

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: rs2229200; hg19: chr17-4801988;