11-62910253-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000738.3(CHRM1):c.848G>T(p.Gly283Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CHRM1 NM_000738.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.458

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHRM1
• BP4: Computational evidence support a benign effect (MetaRNN=0.16424605).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRM1	NM_000738.3	c.848G>T	p.Gly283Val	missense_variant	2/2	ENST00000306960.4
LOC124902683	XR_007062701.1	n.87-350C>A		intron_variant, non_coding_transcript_variant
CHRM1	XM_011544742.3	c.848G>T	p.Gly283Val	missense_variant	2/2
LOC124902683	XR_007062700.1	n.87-350C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRM1	ENST00000306960.4	c.848G>T	p.Gly283Val	missense_variant	2/2	1	NM_000738.3	P1
	ENST00000543624.1	n.71-350C>A		intron_variant, non_coding_transcript_variant		3
CHRM1	ENST00000543973.1	c.848G>T	p.Gly283Val	missense_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250016 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135316

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: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461136 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726884

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.848G>T (p.G283V) alteration is located in exon 2 (coding exon 1) of the CHRM1 gene. This alteration results from a G to T substitution at nucleotide position 848, causing the glycine (G) at amino acid position 283 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.90	N;N
REVEL	Benign	0.15
Sift	Benign	0.14	T;T
Sift4G	Benign	0.061	T;.
Polyphen		0.82	P;.
Vest4		0.15
MutPred		0.30		Gain of solvent accessibility (P = 0.1133);Gain of solvent accessibility (P = 0.1133);
MVP		0.70
MPC		1.6
ClinPred		0.37	T
GERP RS		4.7
Varity_R		0.16
gMVP		0.59

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: rs772689016; hg19: chr11-62677725;