chr8-42708756-C-T

Variant names:

• chr8-42708756-C-T
• rs1334592295
• NM_000749.5:c.92C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000749.5(CHRNB3):​c.92C>T​(p.Ala31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNB3 NM_000749.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.70

Genes affected

CHRNB3 (HGNC:1963): (cholinergic receptor nicotinic beta 3 subunit) The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are (hetero)pentamers composed of homologous subunits. The subunits that make up the muscle and neuronal forms of nAChRs are encoded by separate genes and have different primary structure. There are several subtypes of neuronal nAChRs that vary based on which homologous subunits are arranged around the central channel. They are classified as alpha-subunits if, like muscle alpha-1 (MIM 100690), they have a pair of adjacent cysteines as part of the presumed acetylcholine binding site. Subunits lacking these cysteine residues are classified as beta-subunits (Groot Kormelink and Luyten, 1997 [PubMed 9009220]). Elliott et al. (1996) [PubMed 8906617] stated that the proposed structure for each subunit is a conserved N-terminal extracellular domain followed by 3 conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region.[supplied by OMIM, Apr 2010]

ENSG00000255101 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB3	NM_000749.5	c.92C>T	p.Ala31Val	missense_variant	Exon 2 of 6	ENST00000289957.3	NP_000740.1
CHRNB3	NM_001347717.2	c.-131C>T		5_prime_UTR_variant	Exon 3 of 7		NP_001334646.1
LOC105379396	XR_007060900.1	n.183-2763G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB3	ENST00000289957.3	c.92C>T	p.Ala31Val	missense_variant	Exon 2 of 6	1	NM_000749.5	ENSP00000289957.2
CHRNB3	ENST00000534391.1	c.-131C>T		5_prime_UTR_variant	Exon 3 of 4	3		ENSP00000433913.1
CHRNB3	ENST00000531610.5	n.512C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	4
ENSG00000255101	ENST00000527318.1	n.272-2763G>A		intron_variant	Intron 2 of 2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.21
Sift	Benign	0.075	T
Sift4G	Uncertain	0.022	D
Polyphen		0.92	P
Vest4		0.65
MutPred		0.60		Loss of disorder (P = 0.0632);
MVP		0.56
MPC		0.55
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.18
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs1334592295; hg19: chr8-42563899;