chr17-4899034-G-A

Variant names:

• chr17-4899034-G-A
• rs33978919
• NM_000080.4:c.1293C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000080.4(CHRNE):​c.1293C>T​(p.Ala431Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,609,810 control chromosomes in the GnomAD database, including 18,126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2968 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15158 hom.)
• Consequence: CHRNE NM_000080.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.07
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-4899034-G-A is Benign according to our data. Variant chr17-4899034-G-A is described in ClinVar as Benign. ClinVar VariationId is 128762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.291 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.1293C>T	p.Ala431Ala	synonymous	Exon 11 of 12	NP_000071.1	Q04844

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.1293C>T	p.Ala431Ala	synonymous	Exon 11 of 12	ENSP00000497829.1	Q04844
	CHRNE	ENST00000649830.1		c.360C>T	p.Ala120Ala	synonymous	Exon 11 of 11	ENSP00000496907.1	A0A3B3IRM1
	CHRNE	ENST00000572438.1	TSL:5	n.979C>T		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27646 AN: 152024 Hom.: 2967 Cov.: 33

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.0595

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.146 AC: 35202 AN: 240626 AF XY: 0.144

Gnomad AFR exome AF: 0.301

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.0557

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.140 AC: 204253 AN: 1457666 Hom.: 15158 Cov.: 38 AF XY: 0.140 AC XY: 101479 AN XY: 724782

African (AFR) AF: 0.300 AC: 10049 AN: 33462

American (AMR) AF: 0.165 AC: 7298 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3834 AN: 26038

East Asian (EAS) AF: 0.0921 AC: 3648 AN: 39622

South Asian (SAS) AF: 0.150 AC: 12787 AN: 85484

European-Finnish (FIN) AF: 0.125 AC: 6510 AN: 51892

Middle Eastern (MID) AF: 0.208 AC: 1198 AN: 5764

European-Non Finnish (NFE) AF: 0.135 AC: 150029 AN: 1110876

Other (OTH) AF: 0.148 AC: 8900 AN: 60236

GnomAD4 genome AF: 0.182 AC: 27679 AN: 152144 Hom.: 2968 Cov.: 33 AF XY: 0.179 AC XY: 13325 AN XY: 74408

African (AFR) AF: 0.295 AC: 12244 AN: 41482

American (AMR) AF: 0.181 AC: 2764 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 544 AN: 3470

East Asian (EAS) AF: 0.0598 AC: 309 AN: 5168

South Asian (SAS) AF: 0.149 AC: 717 AN: 4820

European-Finnish (FIN) AF: 0.115 AC: 1215 AN: 10610

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9305 AN: 67988

Other (OTH) AF: 0.186 AC: 393 AN: 2116

Alfa AF: 0.156 Hom.: 939

Bravo AF: 0.192

Asia WGS AF: 0.130 AC: 452 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.5
DANN	Benign	0.93
PhyloP100		-2.1
PromoterAI		-0.0059	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33978919; hg19: chr17-4802329; COSMIC: COSV53416641; COSMIC: COSV53416641;