rs139190636

Variant names:

• chr2-232531555-G-A
• rs139190636
• NM_000751.3:c.946G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_000751.3(CHRND):​c.946G>A​(p.Gly316Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,614,070 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.30
• Publications: 0 publications found

Genes affected

CHRND (HGNC:1965): (cholinergic receptor nicotinic delta subunit) The acetylcholine receptor of muscle has 5 subunits of 4 different types: 2 alpha and 1 each of beta, gamma and delta subunits. After acetylcholine binding, the receptor undergoes an extensive conformation change that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. Defects in this gene are a cause of multiple pterygium syndrome lethal type (MUPSL), congenital myasthenic syndrome slow-channel type (SCCMS), and congenital myasthenic syndrome fast-channel type (FCCMS). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

CHRND Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 3A

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 3B

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• congenital myasthenic syndrome 3C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11711115).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000302 (46/152276) while in subpopulation AFR AF = 0.000963 (40/41546). AF 95% confidence interval is 0.000726. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000751.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	NM_000751.3	MANE Select	c.946G>A	p.Gly316Ser	missense	Exon 9 of 12	NP_000742.1
	CHRND	NM_001256657.2		c.901G>A	p.Gly301Ser	missense	Exon 8 of 11	NP_001243586.1
	CHRND	NM_001311196.2		c.643G>A	p.Gly215Ser	missense	Exon 9 of 12	NP_001298125.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	ENST00000258385.8	TSL:1 MANE Select	c.946G>A	p.Gly316Ser	missense	Exon 9 of 12	ENSP00000258385.3
	CHRND	ENST00000543200.5	TSL:2	c.901G>A	p.Gly301Ser	missense	Exon 8 of 11	ENSP00000438380.1
	CHRND	ENST00000955151.1		c.745G>A	p.Gly249Ser	missense	Exon 8 of 11	ENSP00000625210.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251452 AF XY: 0.000132

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461794 Hom.: 0 Cov.: 33 AF XY: 0.0000509 AC XY: 37 AN XY: 727206

African (AFR) AF: 0.00105 AC: 35 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86252

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112002

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152276 Hom.: 0 Cov.: 31 AF XY: 0.000296 AC XY: 22 AN XY: 74450

African (AFR) AF: 0.000963 AC: 40 AN: 41546

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.000291

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	Lethal multiple pterygium syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.71	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.031	D
Polyphen		0.97	D
Vest4		0.41
MVP		0.89
MPC		0.77
ClinPred		0.094	T
GERP RS		6.1
Varity_R		0.27
gMVP		0.67
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139190636; hg19: chr2-233396265;