rs754133410

Variant names:

• chr20-63349876-G-C
• rs754133410
• NM_000744.7:c.1535C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000744.7(CHRNA4):​c.1535C>G​(p.Ser512Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000971 in 1,442,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.72
• Publications: 0 publications found

Genes affected

CHRNA4 (HGNC:1958): (cholinergic receptor nicotinic alpha 4 subunit) This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

CHRNA4 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25825393).
• BP6: Variant 20-63349876-G-C is Benign according to our data. Variant chr20-63349876-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 568165.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000744.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	NM_000744.7	MANE Select	c.1535C>G	p.Ser512Cys	missense	Exon 5 of 6	NP_000735.1
	CHRNA4	NM_001256573.2		c.1007C>G	p.Ser336Cys	missense	Exon 5 of 6	NP_001243502.1
	CHRNA4	NR_046317.2		n.1744C>G		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.1535C>G	p.Ser512Cys	missense	Exon 5 of 6	ENSP00000359285.4
	CHRNA4	ENST00000463705.5	TSL:1	n.2183C>G		non_coding_transcript_exon	Exon 4 of 5
	CHRNA4	ENST00000467563.3	TSL:1	n.1605C>G		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000564 AC: 13 AN: 230396 AF XY: 0.0000479

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000971 AC: 14 AN: 1442148 Hom.: 0 Cov.: 83 AF XY: 0.00000980 AC XY: 7 AN XY: 714526

African (AFR) AF: 0.00 AC: 0 AN: 33080

American (AMR) AF: 0.000323 AC: 14 AN: 43394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25266

East Asian (EAS) AF: 0.00 AC: 0 AN: 39276

South Asian (SAS) AF: 0.00 AC: 0 AN: 84172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100828

Other (OTH) AF: 0.00 AC: 0 AN: 59330

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000249 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant nocturnal frontal lobe epilepsy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.7
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.33
Sift	Benign	0.088	T
Sift4G	Benign	0.10	T
Polyphen		0.79	P
Vest4		0.36
MutPred		0.37		Loss of glycosylation at S512 (P = 0.0112)
MVP		0.87
MPC		1.1
ClinPred		0.086	T
GERP RS		2.2
Varity_R		0.042
gMVP		0.37
Mutation Taster		=90/10	polymorphism

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: rs754133410; hg19: chr20-61981228;