chr8-27459928-G-T

Variant names:

• chr8-27459928-G-T
• rs1057137
• NM_000742.4:c.*1701C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000742.4(CHRNA2):​c.*1701C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 152,556 control chromosomes in the GnomAD database, including 14,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14352 hom., cov: 31)
  • Exomes 𝑓: 0.29 (28 hom.)
• Consequence: CHRNA2 NM_000742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.183
• Publications: 13 publications found

Genes affected

CHRNA2 (HGNC:1956): (cholinergic receptor nicotinic alpha 2 subunit) Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels formed by a pentameric arrangement of alpha and beta subunits to create distinct muscle and neuronal receptors. Neuronal receptors are found throughout the peripheral and central nervous system where they are involved in fast synaptic transmission. This gene encodes an alpha subunit that is widely expressed in the brain. The proposed structure for nAChR subunits is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. Mutations in this gene cause autosomal dominant nocturnal frontal lobe epilepsy type 4. Single nucleotide polymorphisms (SNPs) in this gene have been associated with nicotine dependence. [provided by RefSeq, Nov 2009]

CHRNA2 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• benign familial infantile epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-27459928-G-T is Benign according to our data. Variant chr8-27459928-G-T is described in ClinVar as [Benign]. Clinvar id is 362665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.*1701C>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.*1701C>A		3_prime_UTR_variant	Exon 7 of 7	5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64095 AN: 151814 Hom.: 14340 Cov.: 31

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.285 AC: 178 AN: 624 Hom.: 28 Cov.: 0 AF XY: 0.300 AC XY: 137 AN XY: 456

African (AFR) AF: 0.643 AC: 9 AN: 14

American (AMR) AF: 0.333 AC: 2 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 2 AN: 6

East Asian (EAS) AF: 0.0714 AC: 2 AN: 28

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.333 AC: 14 AN: 42

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.288 AC: 136 AN: 472

Other (OTH) AF: 0.283 AC: 13 AN: 46

GnomAD4 genome AF: 0.422 AC: 64127 AN: 151932 Hom.: 14352 Cov.: 31 AF XY: 0.417 AC XY: 30927 AN XY: 74254

African (AFR) AF: 0.568 AC: 23506 AN: 41396

American (AMR) AF: 0.379 AC: 5790 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 957 AN: 3470

East Asian (EAS) AF: 0.180 AC: 926 AN: 5146

South Asian (SAS) AF: 0.430 AC: 2069 AN: 4812

European-Finnish (FIN) AF: 0.306 AC: 3244 AN: 10590

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26191 AN: 67938

Other (OTH) AF: 0.393 AC: 829 AN: 2108

Alfa AF: 0.389 Hom.: 10268

Bravo AF: 0.434

Asia WGS AF: 0.341 AC: 1189 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant nocturnal frontal lobe epilepsy 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.51
PhyloP100		0.18
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: rs1057137; hg19: chr8-27317445;