11-3666546-G-C

Variant names:

• chr11-3666546-G-C
• rs1475442790
• NM_020402.4:c.914C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020402.4(CHRNA10):​c.914C>G​(p.Thr305Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,400,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHRNA10 NM_020402.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27207693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA10	NM_020402.4	c.914C>G	p.Thr305Ser	missense_variant	Exon 5 of 5	ENST00000250699.2	NP_065135.2
CHRNA10	NM_001303034.2	c.296C>G	p.Thr99Ser	missense_variant	Exon 5 of 5		NP_001289963.1
CHRNA10	NM_001303035.2	c.296C>G	p.Thr99Ser	missense_variant	Exon 5 of 5		NP_001289964.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA10	ENST00000250699.2	c.914C>G	p.Thr305Ser	missense_variant	Exon 5 of 5	1	NM_020402.4	ENSP00000250699.2
CHRNA10	ENST00000534359.1	c.367C>G	p.Leu123Val	missense_variant	Exon 5 of 5	1		ENSP00000437107.1
CHRNA10	ENST00000526599.1	n.*685C>G		non_coding_transcript_exon_variant	Exon 5 of 5	1		ENSP00000432757.1
CHRNA10	ENST00000526599.1	n.*685C>G		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000432757.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000490 AC: 1 AN: 204280 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 108648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000209

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1400972 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689412

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.26e-7

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.914C>G (p.T305S) alteration is located in exon 5 (coding exon 5) of the CHRNA10 gene. This alteration results from a C to G substitution at nucleotide position 914, causing the threonine (T) at amino acid position 305 to be replaced by a serine (S). 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	Benign	0.31
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Benign	0.97
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.21	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.26
Vest4		0.13
MutPred		0.24		Loss of glycosylation at P122 (P = 0.0902);
MVP		0.89
ClinPred		0.77	D
GERP RS		5.5

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: rs1475442790; hg19: chr11-3687776;