chr8-42708739-C-T

Variant names:

• chr8-42708739-C-T
• rs79124649
• NM_000749.5:c.75C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001347717.2(CHRNB3):​c.-148C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,942 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: CHRNB3 NM_001347717.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.44
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-42708739-C-T is Benign according to our data. Variant chr8-42708739-C-T is described in ClinVar as Benign. ClinVar VariationId is 788867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0111 (1693/152192) while in subpopulation AFR AF = 0.039 (1618/41520). AF 95% confidence interval is 0.0374. There are 34 homozygotes in GnomAd4. There are 802 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347717.2. 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
	CHRNB3	NM_000749.5	MANE Select	c.75C>T	p.Ile25Ile	synonymous	Exon 2 of 6	NP_000740.1	Q05901
	CHRNB3	NM_001347717.2		c.-148C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 7	NP_001334646.1
	CHRNB3	NM_001347717.2		c.-148C>T		5_prime_UTR	Exon 3 of 7	NP_001334646.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB3	ENST00000289957.3	TSL:1 MANE Select	c.75C>T	p.Ile25Ile	synonymous	Exon 2 of 6	ENSP00000289957.2	Q05901
	CHRNB3	ENST00000534391.1	TSL:3	c.-148C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 4	ENSP00000433913.1	A0A1D5RMT8
	CHRNB3	ENST00000534391.1	TSL:3	c.-148C>T		5_prime_UTR	Exon 3 of 4	ENSP00000433913.1	A0A1D5RMT8

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1683 AN: 152074 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00273 AC: 686 AN: 251228 AF XY: 0.00196

Gnomad AFR exome AF: 0.0374

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00112 AC: 1642 AN: 1461750 Hom.: 28 Cov.: 31 AF XY: 0.000950 AC XY: 691 AN XY: 727174

African (AFR) AF: 0.0390 AC: 1307 AN: 33470

American (AMR) AF: 0.00179 AC: 80 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111956

Other (OTH) AF: 0.00278 AC: 168 AN: 60394

GnomAD4 genome AF: 0.0111 AC: 1693 AN: 152192 Hom.: 34 Cov.: 32 AF XY: 0.0108 AC XY: 802 AN XY: 74406

African (AFR) AF: 0.0390 AC: 1618 AN: 41520

American (AMR) AF: 0.00301 AC: 46 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68018

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.00375 Hom.: 5

Bravo AF: 0.0124

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.042
DANN	Benign	0.80
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs79124649; hg19: chr8-42563882;