chr17-4899386-T-TGGGGCA

Variant names:

• chr17-4899386-T-TGGGGCA
• rs761361955
• NM_000080.4:c.1033-8_1033-3dupTGCCCC

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_000080.4(CHRNE):​c.1033-8_1033-3dupTGCCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,533,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: CHRNE NM_000080.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0980
• 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]

C17orf107 (HGNC:37238): (chromosome 17 open reading frame 107)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 17-4899386-T-TGGGGCA is Benign according to our data. Variant chr17-4899386-T-TGGGGCA is described in ClinVar as Likely_benign. ClinVar VariationId is 465850.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 = 0.00122 (185/152102) while in subpopulation AFR AF = 0.00356 (148/41540). AF 95% confidence interval is 0.00309. There are 0 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1033-8_1033-3dupTGCCCC		splice_region intron	N/A	NP_000071.1	Q04844
	C17orf107	NM_001145536.2	MANE Select	c.-377_-376insGGGGCA		upstream_gene	N/A	NP_001139008.1	Q6ZR85

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.1033-3_1033-2insTGCCCC		splice_region intron	N/A	ENSP00000497829.1	Q04844
	CHRNE	ENST00000649830.1		c.100-3_100-2insTGCCCC		splice_region intron	N/A	ENSP00000496907.1	A0A3B3IRM1
	CHRNE	ENST00000572438.1	TSL:5	n.719-3_719-2insTGCCCC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 151986 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000558 AC: 74 AN: 132540 AF XY: 0.000549

Gnomad AFR exome AF: 0.00482

Gnomad AMR exome AF: 0.000577

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000401

Gnomad OTH exome AF: 0.000257

GnomAD4 exome AF: 0.000232 AC: 320 AN: 1381788 Hom.: 0 Cov.: 35 AF XY: 0.000220 AC XY: 150 AN XY: 681866

African (AFR) AF: 0.00272 AC: 85 AN: 31250

American (AMR) AF: 0.000356 AC: 12 AN: 33698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24408

East Asian (EAS) AF: 0.000864 AC: 31 AN: 35886

South Asian (SAS) AF: 0.000127 AC: 10 AN: 78848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39382

Middle Eastern (MID) AF: 0.000425 AC: 2 AN: 4708

European-Non Finnish (NFE) AF: 0.000140 AC: 151 AN: 1076248

Other (OTH) AF: 0.000506 AC: 29 AN: 57360

GnomAD4 genome AF: 0.00122 AC: 185 AN: 152102 Hom.: 0 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74370

African (AFR) AF: 0.00356 AC: 148 AN: 41540

American (AMR) AF: 0.000457 AC: 7 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5154

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.0000947 AC: 1 AN: 10558

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

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67942

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000192 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	CHRNE-related disorder (1)
-	-	1	Congenital myasthenic syndrome 4A (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.098
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs761361955; hg19: chr17-4802681;