NM_000749.5:c.70T>C

Variant names:

• chr8-42708734-T-C
• rs1322281387
• NM_000749.5:c.70T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000749.5(CHRNB3):​c.70T>C​(p.Ser24Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNB3 NM_000749.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.60

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16537955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB3	NM_000749.5	c.70T>C	p.Ser24Pro	missense_variant	Exon 2 of 6	ENST00000289957.3	NP_000740.1
CHRNB3	NM_001347717.2	c.-153T>C		5_prime_UTR_variant	Exon 3 of 7		NP_001334646.1
LOC105379396	XR_007060900.1	n.183-2741A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB3	ENST00000289957.3	c.70T>C	p.Ser24Pro	missense_variant	Exon 2 of 6	1	NM_000749.5	ENSP00000289957.2
CHRNB3	ENST00000534391.1	c.-153T>C		5_prime_UTR_variant	Exon 3 of 4	3		ENSP00000433913.1
CHRNB3	ENST00000531610.5	n.490T>C		non_coding_transcript_exon_variant	Exon 4 of 4	4
ENSG00000255101	ENST00000527318.1	n.272-2741A>G		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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.70T>C (p.S24P) alteration is located in exon 2 (coding exon 2) of the CHRNB3 gene. This alteration results from a T to C substitution at nucleotide position 70, causing the serine (S) at amino acid position 24 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.19
Sift	Benign	0.11	T
Sift4G	Benign	0.27	T
Polyphen		0.032	B
Vest4		0.37
MutPred		0.24		Gain of relative solvent accessibility (P = 0.09);
MVP		0.76
MPC		0.29
ClinPred		0.57	D
GERP RS		4.6
Varity_R		0.14
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1322281387; hg19: chr8-42563877;