11-62910863-T-G

Position:

• chr11-62910863-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000738.3(CHRM1):​c.238A>C​(p.Asn80His) 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: CHRM1 NM_000738.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

Genes affected

CHRM1 (HGNC:1950): (cholinergic receptor muscarinic 1) The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The muscarinic cholinergic receptor 1 is involved in mediation of vagally-induced bronchoconstriction and in the acid secretion of the gastrointestinal tract. The gene encoding this receptor is localized to 11q13. [provided by RefSeq, Jul 2008]

ENSG00000257002 (HGNC:58194):

LOC124902683 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRM1	NM_000738.3	c.238A>C	p.Asn80His	missense_variant	2/2	ENST00000306960.4	NP_000729.2
CHRM1	XM_011544742.3	c.238A>C	p.Asn80His	missense_variant	2/2		XP_011543044.1
LOC124902683	XR_007062700.1	n.329+18T>G		intron_variant
LOC124902683	XR_007062701.1	n.329+18T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRM1	ENST00000306960.4	c.238A>C	p.Asn80His	missense_variant	2/2	1	NM_000738.3	ENSP00000306490.3
CHRM1	ENST00000543973.1	c.238A>C	p.Asn80His	missense_variant	3/3	5		ENSP00000441188.1
CHRM1	ENST00000536524.1	c.238A>C	p.Asn80His	missense_variant	2/2	4		ENSP00000444482.1
ENSG00000257002	ENST00000543624.1	n.313+18T>G		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 23, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with CHRM1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 80 of the CHRM1 protein (p.Asn80His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.5	M;M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0080	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.86
MutPred		0.64		Loss of glycosylation at T76 (P = 0.2626);Loss of glycosylation at T76 (P = 0.2626);Loss of glycosylation at T76 (P = 0.2626);
MVP		0.85
MPC		2.0
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.77
gMVP		0.89

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: chr11-62678335;