1-154568046-T-A

Position:

• chr1-154568046-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000748.3(CHRNB2):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNB2 NM_000748.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.20

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNB2	NM_000748.3	c.2T>A	p.Met1?	start_lost	1/6	ENST00000368476.4	NP_000739.1
CHRNB2	XR_001736952.3	n.269T>A		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNB2	ENST00000368476.4	c.2T>A	p.Met1?	start_lost	1/6	1	NM_000748.3	ENSP00000357461.3
CHRNB2	ENST00000637900.1	c.2T>A	p.Met1?	start_lost	1/6	5		ENSP00000490474.1
CHRNB2	ENST00000636034.1	n.2T>A		non_coding_transcript_exon_variant	1/9	5		ENSP00000489703.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441432 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715796

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 26, 2024

Variant summary: CHRNB2 c.2T>A (p.Met1?, aka p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The first potential downstream in-frame start codon (ATG) is located at Met61, which is not a known initiation codon in alternative transcripts. To our knowledge, no pathogenic missense/in-frame variants have been reported upstream of Met61 (ClinVar). The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position, however other start-loss variants are reported in heterozygous carriers. To our knowledge, no occurrence of c.2T>A in individuals affected with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy 3 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1475973). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2022

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 1475973). This variant has not been reported in the literature in individuals affected with CHRNB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CHRNB2 mRNA. The next in-frame methionine is located at codon 61. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.22	T
PROVEAN	Benign	-1.0	N;.
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.72	P;.
Vest4		0.93
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0117);Gain of catalytic residue at M1 (P = 0.0117);
MVP		0.95
ClinPred		0.84	D
GERP RS		4.4
Varity_R		0.91
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-154540522;