rs6739001

Positions:

• chr2-174748749-T-A

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.1073A>T​(p.Asp358Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,614,218 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (86 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (72 hom.)
• Consequence: CHRNA1 ENST00000348749.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.60

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 (MetaRNN=0.0027716756).
• BP6: Variant 2-174748749-T-A is Benign according to our data. Variant chr2-174748749-T-A is described in ClinVar as [Benign]. Clinvar id is 128733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.1073A>T	p.Asp358Val	missense_variant	8/9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.1148A>T	p.Asp383Val	missense_variant	9/10		NP_001034612.1
CHRNA1	XM_017003256.2	c.1169A>T	p.Asp390Val	missense_variant	8/9		XP_016858745.1
CHRNA1	XM_017003257.2	c.1094A>T	p.Asp365Val	missense_variant	7/8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.1073A>T	p.Asp358Val	missense_variant	8/9	1	NM_000079.4	ENSP00000261008	P1
	ENST00000442996.1	n.321+18925T>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2879 AN: 152212 Hom.: 86 Cov.: 33

Gnomad AFR AF: 0.0657

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00778

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00473 AC: 1188 AN: 251410 Hom.: 42 AF XY: 0.00363 AC XY: 493 AN XY: 135870

Gnomad AFR exome AF: 0.0661

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00178 AC: 2597 AN: 1461888 Hom.: 72 Cov.: 33 AF XY: 0.00154 AC XY: 1122 AN XY: 727242

Gnomad4 AFR exome AF: 0.0645

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000782

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.0189 AC: 2883 AN: 152330 Hom.: 86 Cov.: 33 AF XY: 0.0188 AC XY: 1397 AN XY: 74492

Gnomad4 AFR AF: 0.0656

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00268 Hom.: 7

Bravo AF: 0.0207

ESP6500AA AF: 0.0570 AC: 251

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00575 AC: 698

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Lethal multiple pterygium syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	.;T;T;T
Eigen	Benign	-0.087
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D;D;D;D
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;N;N;.
REVEL	Benign	0.20
Sift	Benign	0.035	D;D;D;.
Sift4G	Benign	0.093	T;T;T;.
Polyphen		0.087	.;B;.;.
Vest4		0.24
MVP		0.87
MPC		0.41
ClinPred		0.028	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.72

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: rs6739001; hg19: chr2-175613477;