rs149292107

chr2-174748683-A-Gchr2-174748683-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000079.4(CHRNA1):c.1139T>C(p.Met380Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,614,220 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00077 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.929

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074359477).
• BP6: Variant 2-174748683-A-G is Benign according to our data. Variant chr2-174748683-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289935.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000775 (118/152328) while in subpopulation AFR AF= 0.00252 (105/41586). AF 95% confidence interval is 0.00213. There are 2 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA1	NM_000079.4	c.1139T>C	p.Met380Thr	missense_variant	8/9	ENST00000348749.9
CHRNA1	NM_001039523.3	c.1214T>C	p.Met405Thr	missense_variant	9/10
CHRNA1	XM_017003256.2	c.1235T>C	p.Met412Thr	missense_variant	8/9
CHRNA1	XM_017003257.2	c.1160T>C	p.Met387Thr	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA1	ENST00000348749.9	c.1139T>C	p.Met380Thr	missense_variant	8/9	1	NM_000079.4	P1
	ENST00000442996.1	n.321+18859A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152210 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251464 Hom.: 0 AF XY: 0.000213 AC XY: 29 AN XY: 135904

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000127 AC: 185 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.0000935 AC XY: 68 AN XY: 727246

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000701

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152328 Hom.: 2 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74488

Gnomad4 AFR AF: 0.00252

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000854

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 27, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2018	- -

Lethal multiple pterygium syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Benign	0.72
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.46	T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0074	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.11	N;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.72	T;T;T;.
Sift4G	Benign	0.63	T;T;T;.
Polyphen		0.0	.;B;.;.
Vest4		0.14
MVP		0.57
MPC		0.29
ClinPred		0.0063	T
GERP RS		3.1
Varity_R		0.056
gMVP		0.45

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: rs149292107; hg19: chr2-175613411;