NM_000748.3:c.-53C>T

Variant names:

• chr1-154567992-C-T
• rs2280781
• NM_000748.3:c.-53C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000748.3(CHRNB2):​c.-53C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0866 in 1,477,526 control chromosomes in the GnomAD database, including 5,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (675 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5292 hom.)
• Consequence: CHRNB2 NM_000748.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.486
• Publications: 7 publications found

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]

CHRNB2 Gene-Disease associations (from GenCC):

• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nocturnal frontal lobe epilepsy 3

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286391 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-154567992-C-T is Benign according to our data. Variant chr1-154567992-C-T is described in ClinVar as [Benign]. Clinvar id is 1291264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB2	NM_000748.3	c.-53C>T		5_prime_UTR_variant	Exon 1 of 6	ENST00000368476.4	NP_000739.1
CHRNB2	XR_001736952.3	n.215C>T		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB2	ENST00000368476.4	c.-53C>T		5_prime_UTR_variant	Exon 1 of 6	1	NM_000748.3	ENSP00000357461.3

Frequencies

GnomAD3 genomes AF: 0.0894 AC: 13595 AN: 152144 Hom.: 676 Cov.: 32

Gnomad AFR AF: 0.0900

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.0551

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.0823

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.0863 AC: 114347 AN: 1325274 Hom.: 5292 Cov.: 28 AF XY: 0.0879 AC XY: 57434 AN XY: 653232

African (AFR) AF: 0.0933 AC: 2528 AN: 27098

American (AMR) AF: 0.102 AC: 2761 AN: 27152

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2605 AN: 22568

East Asian (EAS) AF: 0.124 AC: 3810 AN: 30772

South Asian (SAS) AF: 0.138 AC: 9951 AN: 72068

European-Finnish (FIN) AF: 0.0520 AC: 1873 AN: 36024

Middle Eastern (MID) AF: 0.143 AC: 626 AN: 4370

European-Non Finnish (NFE) AF: 0.0809 AC: 84965 AN: 1050186

Other (OTH) AF: 0.0950 AC: 5228 AN: 55036

GnomAD4 genome AF: 0.0893 AC: 13593 AN: 152252 Hom.: 675 Cov.: 32 AF XY: 0.0891 AC XY: 6630 AN XY: 74426

African (AFR) AF: 0.0899 AC: 3738 AN: 41564

American (AMR) AF: 0.102 AC: 1566 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 457 AN: 3470

East Asian (EAS) AF: 0.119 AC: 617 AN: 5168

South Asian (SAS) AF: 0.147 AC: 709 AN: 4832

European-Finnish (FIN) AF: 0.0551 AC: 585 AN: 10608

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.0823 AC: 5596 AN: 67992

Other (OTH) AF: 0.103 AC: 217 AN: 2112

Alfa AF: 0.0285 Hom.: 21

Bravo AF: 0.0914

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.5
DANN	Benign	0.76
PhyloP100		0.49
PromoterAI		-0.044	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs2280781; hg19: chr1-154540468; COSMIC: COSV63809242; COSMIC: COSV63809242;