2-174756754-C-T

Variant names:

• chr2-174756754-C-T
• rs2646165
• NM_000079.4:c.344+812G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000079.4(CHRNA1):​c.344+812G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 152,130 control chromosomes in the GnomAD database, including 46,881 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (46881 hom., cov: 31)
• Consequence: CHRNA1 NM_000079.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.226
• Publications: 7 publications found

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]

CHRNA1 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 1A

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• myasthenic syndrome, congenital, 1B, fast-channel

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236449 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.344+812G>A		intron_variant	Intron 4 of 8	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.419+812G>A		intron_variant	Intron 5 of 9		NP_001034612.1
CHRNA1	XM_017003256.2	c.440+812G>A		intron_variant	Intron 4 of 8		XP_016858745.1
CHRNA1	XM_017003257.2	c.365+812G>A		intron_variant	Intron 3 of 7		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.344+812G>A		intron_variant	Intron 4 of 8	1	NM_000079.4	ENSP00000261008.5

Frequencies

GnomAD3 genomes AF: 0.763 AC: 115915 AN: 152012 Hom.: 46876 Cov.: 31

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.868

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.936

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.932

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.874

Gnomad OTH AF: 0.792

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.762 AC: 115956 AN: 152130 Hom.: 46881 Cov.: 31 AF XY: 0.767 AC XY: 57062 AN XY: 74396

African (AFR) AF: 0.465 AC: 19263 AN: 41412

American (AMR) AF: 0.870 AC: 13312 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2930 AN: 3470

East Asian (EAS) AF: 0.936 AC: 4846 AN: 5176

South Asian (SAS) AF: 0.746 AC: 3598 AN: 4822

European-Finnish (FIN) AF: 0.932 AC: 9899 AN: 10618

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.874 AC: 59413 AN: 68012

Other (OTH) AF: 0.787 AC: 1666 AN: 2116

Alfa AF: 0.848 Hom.: 108111

Bravo AF: 0.748

Asia WGS AF: 0.790 AC: 2751 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.70
PhyloP100		-0.23
Mutation Taster		=100/0	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: rs2646165; hg19: chr2-175621482;