rs7560774

chr2-174764293-C-Achr2-174764293-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000079.4(CHRNA1):c.43+59G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,553,240 control chromosomes in the GnomAD database, including 161,283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11733 hom., cov: 32)
  • Exomes 𝑓: 0.45 (149550 hom.)
• Consequence: CHRNA1 NM_000079.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.779

Genes affected

CHRNA1 (HGNC:1955): (cholinergic receptor nicotinic alpha 1 subunit) The muscle acetylcholine receptor consiststs of 5 subunits of 4 different types: 2 alpha subunits and 1 each of the beta, gamma, and delta subunits. This gene encodes an alpha subunit that plays a role in acetlycholine binding/channel gating. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2012]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-174764293-C-A is Benign according to our data. Variant chr2-174764293-C-A is described in ClinVar as [Benign]. Clinvar id is 680121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-174764293-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA1	NM_000079.4	c.43+59G>T		intron_variant		ENST00000348749.9
CHRNA1	NM_001039523.3	c.43+59G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA1	ENST00000348749.9	c.43+59G>T		intron_variant		1	NM_000079.4	P1
	ENST00000442996.1	n.322-8456C>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54647 AN: 151930 Hom.: 11737 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.423

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.410

GnomAD4 exome AF: 0.453 AC: 634385 AN: 1401190 Hom.: 149550 AF XY: 0.448 AC XY: 312271 AN XY: 696458

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.410

Gnomad4 ASJ exome AF: 0.544

Gnomad4 EAS exome AF: 0.216

Gnomad4 SAS exome AF: 0.266

Gnomad4 FIN exome AF: 0.481

Gnomad4 NFE exome AF: 0.485

Gnomad4 OTH exome AF: 0.437

GnomAD4 genome AF: 0.359 AC: 54657 AN: 152050 Hom.: 11733 Cov.: 32 AF XY: 0.356 AC XY: 26440 AN XY: 74312

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.432

Gnomad4 ASJ AF: 0.531

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.477

Gnomad4 NFE AF: 0.477

Gnomad4 OTH AF: 0.407

Alfa AF: 0.459 Hom.: 10722

Bravo AF: 0.349

Asia WGS AF: 0.221 AC: 771 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myasthenic syndrome, congenital, 1B, fast-channel Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Lethal multiple pterygium syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Congenital myasthenic syndrome 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.90
Dann	Benign	0.70

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: rs7560774; hg19: chr2-175629021; COSMIC: COSV53683582;