11-3667268-C-T

Variant names:

• chr11-3667268-C-T
• rs769677015
• NM_020402.4:c.859G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020402.4(CHRNA10):​c.859G>A​(p.Glu287Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000097 in 1,443,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: CHRNA10 NM_020402.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

CHRNA10 (HGNC:13800): (cholinergic receptor nicotinic alpha 10 subunit) Predicted to enable acetylcholine-gated cation-selective channel activity. Acts upstream of or within positive regulation of cytosolic calcium ion concentration. Predicted to be located in membrane. Predicted to be active in cholinergic synapse and neuron projection. Predicted to be integral component of postsynaptic specialization membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA10	NM_020402.4	c.859G>A	p.Glu287Lys	missense_variant	Exon 4 of 5	ENST00000250699.2	NP_065135.2
CHRNA10	NM_001303034.2	c.241G>A	p.Glu81Lys	missense_variant	Exon 4 of 5		NP_001289963.1
CHRNA10	NM_001303035.2	c.241G>A	p.Glu81Lys	missense_variant	Exon 4 of 5		NP_001289964.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA10	ENST00000250699.2	c.859G>A	p.Glu287Lys	missense_variant	Exon 4 of 5	1	NM_020402.4	ENSP00000250699.2
CHRNA10	ENST00000534359.1	c.312G>A	p.Pro104Pro	synonymous_variant	Exon 4 of 5	1		ENSP00000437107.1
CHRNA10	ENST00000526599.1	n.*630G>A		non_coding_transcript_exon_variant	Exon 4 of 5	1		ENSP00000432757.1
CHRNA10	ENST00000526599.1	n.*630G>A		3_prime_UTR_variant	Exon 4 of 5	1		ENSP00000432757.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000317 AC: 7 AN: 220588 Hom.: 0 AF XY: 0.0000328 AC XY: 4 AN XY: 121990

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000597

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000669

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000200

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.00000970 AC: 14 AN: 1443010 Hom.: 0 Cov.: 32 AF XY: 0.00000557 AC XY: 4 AN XY: 718162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000453

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000721

Gnomad4 OTH exome AF: 0.0000500

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.859G>A (p.E287K) alteration is located in exon 4 (coding exon 4) of the CHRNA10 gene. This alteration results from a G to A substitution at nucleotide position 859, causing the glutamic acid (E) at amino acid position 287 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.068	D
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.92
MutPred		0.78		Gain of ubiquitination at E287 (P = 0.0177);
MVP		0.80
MPC		0.63
ClinPred		0.81	D
GERP RS		5.0
Varity_R		0.91
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: rs769677015; hg19: chr11-3688498; COSMIC: COSV105860209; COSMIC: COSV105860209;