NM_000080.4:c.1220-5G>A

Variant names:

• chr17-4899112-C-T
• rs188564977
• NM_000080.4:c.1220-5G>A

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.1220-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000553 in 1,606,098 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: CHRNE NM_000080.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001060
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.53
• Publications: 0 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=-0.86).
• BP6: Variant 17-4899112-C-T is Benign according to our data. Variant chr17-4899112-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 323982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00262 (397/151502) while in subpopulation AFR AF = 0.00893 (369/41324). AF 95% confidence interval is 0.00818. There are 1 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	NM_000080.4	MANE Select	c.1220-5G>A		splice_region intron	N/A	NP_000071.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.1220-5G>A		splice_region intron	N/A	ENSP00000497829.1
	CHRNE	ENST00000649830.1		c.287-5G>A		splice_region intron	N/A	ENSP00000496907.1
	CHRNE	ENST00000572438.1	TSL:5	n.906-5G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 395 AN: 151384 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.0000950

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.000638 AC: 146 AN: 228696 AF XY: 0.000485

Gnomad AFR exome AF: 0.00906

Gnomad AMR exome AF: 0.000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000541

Gnomad NFE exome AF: 0.000148

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000338 AC: 491 AN: 1454596 Hom.: 2 Cov.: 36 AF XY: 0.000295 AC XY: 213 AN XY: 723252

African (AFR) AF: 0.00864 AC: 289 AN: 33430

American (AMR) AF: 0.000430 AC: 19 AN: 44150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85388

European-Finnish (FIN) AF: 0.0000398 AC: 2 AN: 50202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000144 AC: 160 AN: 1110080

Other (OTH) AF: 0.000333 AC: 20 AN: 60094

GnomAD4 genome AF: 0.00262 AC: 397 AN: 151502 Hom.: 1 Cov.: 33 AF XY: 0.00248 AC XY: 184 AN XY: 74078

African (AFR) AF: 0.00893 AC: 369 AN: 41324

American (AMR) AF: 0.000591 AC: 9 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4772

European-Finnish (FIN) AF: 0.0000950 AC: 1 AN: 10530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67748

Other (OTH) AF: 0.000477 AC: 1 AN: 2098

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00306

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.91
PhyloP100		-1.5
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.050		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: rs188564977; hg19: chr17-4802407;