2-174764872-T-C

Variant names:

• chr2-174764872-T-C
• rs16862847
• ENST00000442996.1:n.322-7877T>C

Variant summary

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

The ENST00000442996.1(ENSG00000236449):​n.322-7877T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 152,176 control chromosomes in the GnomAD database, including 1,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: 𝑓 0.14 (1555 hom., cov: 32)
• Consequence: ENSG00000236449 ENST00000442996.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.116
• Publications: 6 publications found

Genes affected

ENSG00000236449 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-174764872-T-C is Benign according to our data. Variant chr2-174764872-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000442996.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000236449	ENST00000442996.1	TSL:1	n.322-7877T>C		intron	N/A
	CHRNA1	ENST00000636168.2	TSL:5	c.-446-5239A>G		intron	N/A	ENSP00000490338.2
	ENSG00000236449	ENST00000842845.1		n.326+35048T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20585 AN: 152058 Hom.: 1553 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0886

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.0562

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.0678

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.140

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

GnomAD4 genome AF: 0.135 AC: 20610 AN: 152176 Hom.: 1555 Cov.: 32 AF XY: 0.134 AC XY: 9952 AN XY: 74406

African (AFR) AF: 0.188 AC: 7783 AN: 41502

American (AMR) AF: 0.0885 AC: 1354 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 485 AN: 3470

East Asian (EAS) AF: 0.0559 AC: 289 AN: 5168

South Asian (SAS) AF: 0.249 AC: 1200 AN: 4816

European-Finnish (FIN) AF: 0.0678 AC: 719 AN: 10610

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8308 AN: 67996

Other (OTH) AF: 0.145 AC: 306 AN: 2116

Alfa AF: 0.128 Hom.: 1858

Bravo AF: 0.135

Asia WGS AF: 0.185 AC: 640 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Lethal multiple pterygium syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.6
DANN	Benign	0.65
PhyloP100		-0.12
PromoterAI		-0.32	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16862847; hg19: chr2-175629600;