rs75492003

Variant names:

• chr17-4899152-G-A
• rs75492003
• NM_000080.4:c.1220-45C>T

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.1220-45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,595,022 control chromosomes in the GnomAD database, including 15,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1491 hom., cov: 33)
  • Exomes 𝑓: 0.10 (13977 hom.)
• Consequence: CHRNE NM_000080.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.87
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-4899152-G-A is Benign according to our data. Variant chr17-4899152-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.488 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.1220-45C>T		intron	N/A	NP_000071.1	Q04844

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.1220-45C>T		intron	N/A	ENSP00000497829.1	Q04844
	CHRNE	ENST00000649830.1		c.287-45C>T		intron	N/A	ENSP00000496907.1	A0A3B3IRM1
	CHRNE	ENST00000572438.1	TSL:5	n.906-45C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16049 AN: 151784 Hom.: 1498 Cov.: 33

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0719

Gnomad OTH AF: 0.0907

GnomAD2 exomes AF: 0.161 AC: 33452 AN: 207834 AF XY: 0.167

Gnomad AFR exome AF: 0.0799

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.505

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.0746

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.103 AC: 148301 AN: 1443122 Hom.: 13977 Cov.: 36 AF XY: 0.110 AC XY: 78524 AN XY: 716756

African (AFR) AF: 0.0759 AC: 2517 AN: 33154

American (AMR) AF: 0.133 AC: 5662 AN: 42576

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3330 AN: 25750

East Asian (EAS) AF: 0.475 AC: 18515 AN: 38980

South Asian (SAS) AF: 0.332 AC: 27908 AN: 84088

European-Finnish (FIN) AF: 0.107 AC: 5084 AN: 47586

Middle Eastern (MID) AF: 0.129 AC: 738 AN: 5732

European-Non Finnish (NFE) AF: 0.0699 AC: 77308 AN: 1105518

Other (OTH) AF: 0.121 AC: 7239 AN: 59738

GnomAD4 genome AF: 0.106 AC: 16038 AN: 151900 Hom.: 1491 Cov.: 33 AF XY: 0.116 AC XY: 8618 AN XY: 74222

African (AFR) AF: 0.0760 AC: 3151 AN: 41484

American (AMR) AF: 0.110 AC: 1679 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 477 AN: 3472

East Asian (EAS) AF: 0.504 AC: 2577 AN: 5116

South Asian (SAS) AF: 0.350 AC: 1691 AN: 4826

European-Finnish (FIN) AF: 0.129 AC: 1359 AN: 10558

Middle Eastern (MID) AF: 0.0959 AC: 28 AN: 292

European-Non Finnish (NFE) AF: 0.0718 AC: 4873 AN: 67852

Other (OTH) AF: 0.0940 AC: 198 AN: 2106

Alfa AF: 0.0908 Hom.: 150

Bravo AF: 0.100

Asia WGS AF: 0.399 AC: 1384 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.023
DANN	Benign	0.75
PhyloP100		-5.9
PromoterAI		-0.013	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: rs75492003; hg19: chr17-4802447;