8-42756639-T-G

Variant names:

• chr8-42756639-T-G
• NM_004198.3:c.560A>C

Variant summary

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

The NM_004198.3(CHRNA6):​c.560A>C​(p.Asp187Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNA6 NM_004198.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95

Genes affected

CHRNA6 (HGNC:15963): (cholinergic receptor nicotinic alpha 6 subunit) This gene encodes an alpha subunit of neuronal nicotinic acetylcholine receptors. These receptors consist of five subunits and function as ion channels involved in neurotransmission. The encoded protein is a subunit of neuronal nicotinic acetylcholine receptors that mediate dopaminergic neurotransmission and are activated by acetylcholine and exogenous nicotine. Alternatively spliced transcript variants have been observed for this gene. Single nucleotide polymorphisms in this gene have been associated with both nicotine and alcohol dependence. [provided by RefSeq, Dec 2010]

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, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA6	NM_004198.3	c.560A>C	p.Asp187Ala	missense_variant	Exon 5 of 6	ENST00000276410.7	NP_004189.1
CHRNA6	NM_001199279.1	c.515A>C	p.Asp172Ala	missense_variant	Exon 4 of 5		NP_001186208.1
CHRNA6	XM_047422396.1	c.560A>C	p.Asp187Ala	missense_variant	Exon 6 of 7		XP_047278352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA6	ENST00000276410.7	c.560A>C	p.Asp187Ala	missense_variant	Exon 5 of 6	1	NM_004198.3	ENSP00000276410.3
CHRNA6	ENST00000534622.5	c.515A>C	p.Asp172Ala	missense_variant	Exon 4 of 5	2		ENSP00000433871.1
CHRNA6	ENST00000533810.5	c.323A>C	p.Asp108Ala	missense_variant	Exon 5 of 5	4		ENSP00000434659.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.560A>C (p.D187A) alteration is located in exon 5 (coding exon 5) of the CHRNA6 gene. This alteration results from a A to C substitution at nucleotide position 560, causing the aspartic acid (D) at amino acid position 187 to be replaced by an alanine (A). 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	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.4	D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.70		Loss of ubiquitination at K183 (P = 0.1601);.;.;
MVP		0.95
MPC		0.60
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.73
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-42611782;