2-174748872-T-C

Position:

• chr2-174748872-T-C

Variant summary

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

The ENST00000348749.9(CHRNA1):​c.1003-53A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.924 in 1,605,074 control chromosomes in the GnomAD database, including 687,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58936 hom., cov: 33)
  • Exomes 𝑓: 0.93 (628845 hom.)
• Consequence: CHRNA1 ENST00000348749.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.144

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=-0.86).
• BP6: Variant 2-174748872-T-C is Benign according to our data. Variant chr2-174748872-T-C is described in ClinVar as [Benign]. Clinvar id is 679132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.1003-53A>G		intron_variant		ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.1078-53A>G		intron_variant			NP_001034612.1
CHRNA1	XM_017003256.2	c.1099-53A>G		intron_variant			XP_016858745.1
CHRNA1	XM_017003257.2	c.1024-53A>G		intron_variant			XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.1003-53A>G		intron_variant		1	NM_000079.4	ENSP00000261008	P1
	ENST00000442996.1	n.321+19048T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.874 AC: 132952 AN: 152124 Hom.: 58907 Cov.: 33

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.922

Gnomad AMR AF: 0.937

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.959

Gnomad FIN AF: 0.952

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.894

GnomAD4 exome AF: 0.929 AC: 1350366 AN: 1452832 Hom.: 628845 AF XY: 0.930 AC XY: 672599 AN XY: 722892

Gnomad4 AFR exome AF: 0.691

Gnomad4 AMR exome AF: 0.959

Gnomad4 ASJ exome AF: 0.914

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.953

Gnomad4 FIN exome AF: 0.958

Gnomad4 NFE exome AF: 0.930

Gnomad4 OTH exome AF: 0.927

GnomAD4 genome AF: 0.874 AC: 133037 AN: 152242 Hom.: 58936 Cov.: 33 AF XY: 0.878 AC XY: 65379 AN XY: 74452

Gnomad4 AFR AF: 0.705

Gnomad4 AMR AF: 0.937

Gnomad4 ASJ AF: 0.913

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.959

Gnomad4 FIN AF: 0.952

Gnomad4 NFE AF: 0.931

Gnomad4 OTH AF: 0.895

Alfa AF: 0.836 Hom.: 5136

Bravo AF: 0.865

Asia WGS AF: 0.969 AC: 3372 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

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

- -

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	-0.86
CADD	Benign	5.0
DANN	Benign	0.68

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: rs2646159; hg19: chr2-175613600;