rs1553204449

Positions:

• chr1-154572159-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000748.3(CHRNB2):​c.1336A>G​(p.Ser446Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000144 in 1,384,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S446S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHRNB2 NM_000748.3 missense, splice_region
• Scores: Splicing: ADA: 0.03538
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

Genes affected

CHRNB2 (HGNC:1962): (cholinergic receptor nicotinic beta 2 subunit) Neuronal acetylcholine receptors are homo- or heteropentameric complexes composed of homologous alpha and beta subunits. They belong to a superfamily of ligand-gated ion channels which allow the flow of sodium and potassium across the plasma membrane in response to ligands such as acetylcholine and nicotine. This gene encodes one of several beta subunits. Mutations in this gene are associated with autosomal dominant nocturnal frontal lobe epilepsy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34528965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB2	NM_000748.3	c.1336A>G	p.Ser446Gly	missense_variant, splice_region_variant	5/6	ENST00000368476.4
CHRNB2	XM_017000180.3	c.826A>G	p.Ser276Gly	missense_variant, splice_region_variant	2/3
CHRNB2	XR_001736952.3	n.1603A>G		splice_region_variant, non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB2	ENST00000368476.4	c.1336A>G	p.Ser446Gly	missense_variant, splice_region_variant	5/6	1	NM_000748.3	P4
CHRNB2	ENST00000637900.1	c.1342A>G	p.Ser448Gly	missense_variant, splice_region_variant	5/6	5		A1
CHRNB2	ENST00000636034.1	c.1336A>G	p.Ser446Gly	missense_variant, splice_region_variant, NMD_transcript_variant	5/9	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1384874 Hom.: 0 Cov.: 33 AF XY: 0.00000293 AC XY: 2 AN XY: 683504

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.45
Sift	Benign	0.15	T;.
Sift4G	Benign	0.15	T;.
Polyphen		0.0050	B;.
Vest4		0.53
MutPred		0.47		Gain of catalytic residue at S446 (P = 0.0363);.;
MVP		0.90
MPC		1.0
ClinPred		0.79	D
GERP RS		4.0
Varity_R		0.48
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.035
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553204449; hg19: chr1-154544635;