17-4898730-T-C

Variant names:

• chr17-4898730-T-C
• rs55806270
• NM_000080.4:c.*6A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000080.4(CHRNE):​c.*6A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,608,722 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (48 hom.)
• Consequence: CHRNE NM_000080.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.241
• Publications: 2 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=-0.92).
• BP6: Variant 17-4898730-T-C is Benign according to our data. Variant chr17-4898730-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00459 (699/152190) while in subpopulation NFE AF = 0.00859 (584/67976). AF 95% confidence interval is 0.00801. There are 2 homozygotes in GnomAd4. There are 267 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.*6A>G		3_prime_UTR	Exon 12 of 12	NP_000071.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.*6A>G		3_prime_UTR	Exon 12 of 12	ENSP00000497829.1
	CHRNE	ENST00000649830.1		c.*124A>G		3_prime_UTR	Exon 11 of 11	ENSP00000496907.1
	CHRNE	ENST00000572438.1	TSL:5	n.1174A>G		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 699 AN: 152072 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00859

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00415 AC: 999 AN: 240770 AF XY: 0.00410

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.000747

Gnomad ASJ exome AF: 0.00185

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00302

Gnomad NFE exome AF: 0.00755

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00713 AC: 10391 AN: 1456532 Hom.: 48 Cov.: 34 AF XY: 0.00702 AC XY: 5086 AN XY: 724014

African (AFR) AF: 0.000837 AC: 28 AN: 33454

American (AMR) AF: 0.000843 AC: 37 AN: 43880

Ashkenazi Jewish (ASJ) AF: 0.00247 AC: 64 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.000964 AC: 82 AN: 85100

European-Finnish (FIN) AF: 0.00438 AC: 231 AN: 52748

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5760

European-Non Finnish (NFE) AF: 0.00862 AC: 9572 AN: 1109922

Other (OTH) AF: 0.00611 AC: 368 AN: 60196

GnomAD4 genome AF: 0.00459 AC: 699 AN: 152190 Hom.: 2 Cov.: 33 AF XY: 0.00359 AC XY: 267 AN XY: 74418

African (AFR) AF: 0.00147 AC: 61 AN: 41538

American (AMR) AF: 0.000524 AC: 8 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00859 AC: 584 AN: 67976

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00614 Hom.: 1

Bravo AF: 0.00417

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Congenital myasthenic syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.32
DANN	Benign	0.36
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism

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: rs55806270; hg19: chr17-4802025;