rs2472553

Variant names:

• chr8-27470994-G-A
• rs2472553
• NM_000742.4:c.65C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-27470994-G-A
• chr8-27470994-G-C
• chr8-27470994-G-T

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.65C>T​(p.Thr22Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,613,474 control chromosomes in the GnomAD database, including 19,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2187 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17728 hom.)
• Consequence: CHRNA2 NM_000742.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.296
• Publications: 44 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
• 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 (MetaRNN=0.002926439).
• BP6: Variant 8-27470994-G-A is Benign according to our data. Variant chr8-27470994-G-A is described in ClinVar as Benign. ClinVar VariationId is 128740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

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.65C>T	p.Thr22Ile	missense	Exon 2 of 7	NP_000733.2	Q15822-1
	CHRNA2	NM_001282455.2		c.65C>T	p.Thr22Ile	missense	Exon 2 of 7	NP_001269384.1	Q15822-2
	CHRNA2	NM_001347705.2		c.-363C>T		5_prime_UTR	Exon 2 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.65C>T	p.Thr22Ile	missense	Exon 2 of 7	ENSP00000385026.1	Q15822-1
	CHRNA2	ENST00000523695.5	TSL:1	n.65C>T		non_coding_transcript_exon	Exon 2 of 7	ENSP00000430612.1	E5RJ54
	CHRNA2	ENST00000240132.7	TSL:2	c.65C>T	p.Thr22Ile	missense	Exon 2 of 7	ENSP00000240132.2	Q15822-2

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24048 AN: 152064 Hom.: 2183 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.166 AC: 41628 AN: 250562 AF XY: 0.160

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.0655

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.145 AC: 211462 AN: 1461292 Hom.: 17728 Cov.: 32 AF XY: 0.144 AC XY: 104428 AN XY: 726976

African (AFR) AF: 0.170 AC: 5676 AN: 33466

American (AMR) AF: 0.191 AC: 8559 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 1710 AN: 26128

East Asian (EAS) AF: 0.444 AC: 17610 AN: 39672

South Asian (SAS) AF: 0.127 AC: 10940 AN: 86242

European-Finnish (FIN) AF: 0.164 AC: 8757 AN: 53394

Middle Eastern (MID) AF: 0.0687 AC: 396 AN: 5768

European-Non Finnish (NFE) AF: 0.134 AC: 149139 AN: 1111560

Other (OTH) AF: 0.144 AC: 8675 AN: 60360

GnomAD4 genome AF: 0.158 AC: 24080 AN: 152182 Hom.: 2187 Cov.: 32 AF XY: 0.162 AC XY: 12038 AN XY: 74400

African (AFR) AF: 0.170 AC: 7041 AN: 41532

American (AMR) AF: 0.180 AC: 2746 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 191 AN: 3470

East Asian (EAS) AF: 0.439 AC: 2264 AN: 5162

South Asian (SAS) AF: 0.149 AC: 717 AN: 4828

European-Finnish (FIN) AF: 0.164 AC: 1737 AN: 10584

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9012 AN: 67998

Other (OTH) AF: 0.132 AC: 278 AN: 2110

Alfa AF: 0.141 Hom.: 7838

Bravo AF: 0.160

TwinsUK AF: 0.138 AC: 513

ALSPAC AF: 0.130 AC: 501

ESP6500AA AF: 0.184 AC: 810

ESP6500EA AF: 0.131 AC: 1125

ExAC AF: 0.165 AC: 19975

Asia WGS AF: 0.262 AC: 909 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.121

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.2
DANN	Benign	0.061
DEOGEN2	Benign	0.090	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0096	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.30
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.078
Sift	Benign	1.0	T
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.011
MPC		0.19
ClinPred		0.00054	T
GERP RS		-2.5
Varity_R		0.028
gMVP		0.28
Mutation Taster		=97/3	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: rs2472553; hg19: chr8-27328511; COSMIC: COSV53556702; COSMIC: COSV53556702;