chr2-174748872-T-C

Variant names:

• chr2-174748872-T-C
• rs2646159
• NM_000079.4:c.1003-53A>G

Variant summary

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

The NM_000079.4(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 NM_000079.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.144
• Publications: 8 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)
• myasthenic syndrome, congenital, 1B, fast-channel

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236449 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000079.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA1	NM_000079.4	MANE Select	c.1003-53A>G		intron	N/A	NP_000070.1	Q53SH4
	CHRNA1	NM_001039523.3		c.1078-53A>G		intron	N/A	NP_001034612.1	P02708-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA1	ENST00000348749.9	TSL:1 MANE Select	c.1003-53A>G		intron	N/A	ENSP00000261008.5	P02708-2
	ENSG00000236449	ENST00000442996.1	TSL:1	n.321+19048T>C		intron	N/A
	CHRNA1	ENST00000261007.9	TSL:2	c.1078-53A>G		intron	N/A	ENSP00000261007.5	P02708-1

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

African (AFR) AF: 0.691 AC: 23006 AN: 33276

American (AMR) AF: 0.959 AC: 42714 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 23848 AN: 26098

East Asian (EAS) AF: 1.00 AC: 39555 AN: 39562

South Asian (SAS) AF: 0.953 AC: 81187 AN: 85230

European-Finnish (FIN) AF: 0.958 AC: 46914 AN: 48962

Middle Eastern (MID) AF: 0.932 AC: 4552 AN: 4882

European-Non Finnish (NFE) AF: 0.930 AC: 1032893 AN: 1110180

Other (OTH) AF: 0.927 AC: 55697 AN: 60114

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

African (AFR) AF: 0.705 AC: 29263 AN: 41508

American (AMR) AF: 0.937 AC: 14336 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 3169 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5190 AN: 5192

South Asian (SAS) AF: 0.959 AC: 4626 AN: 4826

European-Finnish (FIN) AF: 0.952 AC: 10097 AN: 10606

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.931 AC: 63348 AN: 68028

Other (OTH) AF: 0.895 AC: 1889 AN: 2110

Alfa AF: 0.817 Hom.: 18131

Bravo AF: 0.865

Asia WGS AF: 0.969 AC: 3372 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital myasthenic syndrome 1A (1)
-	-	1	Lethal multiple pterygium syndrome (1)
-	-	1	Myasthenic syndrome, congenital, 1B, fast-channel (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.0
DANN	Benign	0.68
PhyloP100		0.14
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: rs2646159; hg19: chr2-175613600;