chr8-27463672-G-A

Variant names:

• chr8-27463672-G-A
• rs56229264
• NM_000742.4:c.771C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000742.4(CHRNA2):​c.771C>T​(p.Tyr257Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,614,148 control chromosomes in the GnomAD database, including 252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 33)
  • Exomes 𝑓: 0.016 (231 hom.)
• Consequence: CHRNA2 NM_000742.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.04
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 8-27463672-G-A is Benign according to our data. Variant chr8-27463672-G-A is described in ClinVar as Benign. ClinVar VariationId is 128741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0124 (1881/152260) while in subpopulation NFE AF = 0.0198 (1347/68022). AF 95% confidence interval is 0.0189. There are 21 homozygotes in GnomAd4. There are 888 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1881 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000742.4. 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
	CHRNA2	NM_000742.4	MANE Select	c.771C>T	p.Tyr257Tyr	synonymous	Exon 6 of 7	NP_000733.2
	CHRNA2	NM_001282455.2		c.726C>T	p.Tyr242Tyr	synonymous	Exon 6 of 7	NP_001269384.1
	CHRNA2	NM_001347705.2		c.294C>T	p.Tyr98Tyr	synonymous	Exon 6 of 7	NP_001334634.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.771C>T	p.Tyr257Tyr	synonymous	Exon 6 of 7	ENSP00000385026.1
	CHRNA2	ENST00000523695.5	TSL:1	n.*173C>T		non_coding_transcript_exon	Exon 6 of 7	ENSP00000430612.1
	CHRNA2	ENST00000523695.5	TSL:1	n.*173C>T		3_prime_UTR	Exon 6 of 7	ENSP00000430612.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1883 AN: 152142 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0143 AC: 3592 AN: 251444 AF XY: 0.0149

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0164 AC: 24015 AN: 1461888 Hom.: 231 Cov.: 33 AF XY: 0.0164 AC XY: 11951 AN XY: 727244

African (AFR) AF: 0.00194 AC: 65 AN: 33480

American (AMR) AF: 0.0118 AC: 529 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 519 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00828 AC: 714 AN: 86258

European-Finnish (FIN) AF: 0.0111 AC: 593 AN: 53418

Middle Eastern (MID) AF: 0.0186 AC: 107 AN: 5768

European-Non Finnish (NFE) AF: 0.0184 AC: 20506 AN: 1112012

Other (OTH) AF: 0.0162 AC: 979 AN: 60396

GnomAD4 genome AF: 0.0124 AC: 1881 AN: 152260 Hom.: 21 Cov.: 33 AF XY: 0.0119 AC XY: 888 AN XY: 74442

African (AFR) AF: 0.00289 AC: 120 AN: 41552

American (AMR) AF: 0.00961 AC: 147 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4822

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0198 AC: 1347 AN: 68022

Other (OTH) AF: 0.0138 AC: 29 AN: 2108

Alfa AF: 0.0186 Hom.: 23

Bravo AF: 0.0121

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0225

EpiControl AF: 0.0243

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy (1)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 4 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.75
PhyloP100		3.0
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: rs56229264; hg19: chr8-27321189;