rs2229957

chr2-174749988-G-Achr2-174749988-G-Cchr2-174749988-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000079.4(CHRNA1):c.960C>T(p.His320=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0732 in 1,613,996 control chromosomes in the GnomAD database, including 5,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (827 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4971 hom.)
• Consequence: CHRNA1 NM_000079.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.79

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-174749988-G-A is Benign according to our data. Variant chr2-174749988-G-A is described in ClinVar as [Benign]. Clinvar id is 128735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-174749988-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA1	NM_000079.4	c.960C>T	p.His320=	synonymous_variant	7/9	ENST00000348749.9
CHRNA1	NM_001039523.3	c.1035C>T	p.His345=	synonymous_variant	8/10
CHRNA1	XM_017003256.2	c.1056C>T	p.His352=	synonymous_variant	7/9
CHRNA1	XM_017003257.2	c.981C>T	p.His327=	synonymous_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA1	ENST00000348749.9	c.960C>T	p.His320=	synonymous_variant	7/9	1	NM_000079.4	P1
	ENST00000442996.1	n.321+20164G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0914 AC: 13892 AN: 152038 Hom.: 820 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0640

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.0613

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.0880

GnomAD3 exomes AF: 0.0808 AC: 20297 AN: 251154 Hom.: 1209 AF XY: 0.0863 AC XY: 11719 AN XY: 135730

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.0446

Gnomad ASJ exome AF: 0.0693

Gnomad EAS exome AF: 0.0539

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0653

Gnomad OTH exome AF: 0.0827

GnomAD4 exome AF: 0.0713 AC: 104276 AN: 1461840 Hom.: 4971 Cov.: 34 AF XY: 0.0751 AC XY: 54650 AN XY: 727224

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.0469

Gnomad4 ASJ exome AF: 0.0667

Gnomad4 EAS exome AF: 0.0558

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.0246

Gnomad4 NFE exome AF: 0.0620

Gnomad4 OTH exome AF: 0.0810

GnomAD4 genome AF: 0.0915 AC: 13925 AN: 152156 Hom.: 827 Cov.: 32 AF XY: 0.0916 AC XY: 6815 AN XY: 74390

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0639

Gnomad4 ASJ AF: 0.0683

Gnomad4 EAS AF: 0.0611

Gnomad4 SAS AF: 0.210

Gnomad4 FIN AF: 0.0223

Gnomad4 NFE AF: 0.0662

Gnomad4 OTH AF: 0.0946

Alfa AF: 0.0708 Hom.: 700

Bravo AF: 0.0933

Asia WGS AF: 0.172 AC: 595 AN: 3478

EpiCase AF: 0.0706

EpiControl AF: 0.0701

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Lethal multiple pterygium syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital myasthenic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	10
Dann	Benign	0.88

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: rs2229957; hg19: chr2-175614716; COSMIC: COSV99650186; COSMIC: COSV99650186;