chr2-232531393-C-G

Variant names:

• chr2-232531393-C-G
• rs41265127
• NM_000751.3:c.862C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000751.3(CHRND):​c.862C>G​(p.Gln288Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,613,830 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.87
• Publications: 14 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 3B

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

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000751.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.057361603).
• BP6: Variant 2-232531393-C-G is Benign according to our data. Variant chr2-232531393-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00231 (352/152110) while in subpopulation NFE AF = 0.00312 (212/67970). AF 95% confidence interval is 0.00277. There are 0 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

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.862C>G	p.Gln288Glu	missense	Exon 8 of 12	NP_000742.1	Q07001-1
	CHRND	NM_001256657.2		c.817C>G	p.Gln273Glu	missense	Exon 7 of 11	NP_001243586.1	Q07001-2
	CHRND	NM_001311196.2		c.559C>G	p.Gln187Glu	missense	Exon 8 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.862C>G	p.Gln288Glu	missense	Exon 8 of 12	ENSP00000258385.3	Q07001-1
	CHRND	ENST00000543200.5	TSL:2	c.817C>G	p.Gln273Glu	missense	Exon 7 of 11	ENSP00000438380.1	Q07001-2
	CHRND	ENST00000955151.1		c.661C>G	p.Gln221Glu	missense	Exon 7 of 11	ENSP00000625210.1

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 352 AN: 151992 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00265 AC: 667 AN: 251240 AF XY: 0.00253

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.00333

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00318 AC: 4646 AN: 1461720 Hom.: 11 Cov.: 33 AF XY: 0.00313 AC XY: 2274 AN XY: 727150

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00208 AC: 93 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 309 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00246 AC: 131 AN: 53268

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00350 AC: 3894 AN: 1111992

Other (OTH) AF: 0.00323 AC: 195 AN: 60394

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152110 Hom.: 0 Cov.: 31 AF XY: 0.00212 AC XY: 158 AN XY: 74364

African (AFR) AF: 0.000940 AC: 39 AN: 41508

American (AMR) AF: 0.00183 AC: 28 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4782

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00312 AC: 212 AN: 67970

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00403 Hom.: 1

Bravo AF: 0.00236

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00251 AC: 305

EpiCase AF: 0.00213

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Lethal multiple pterygium syndrome (2)
-	-	2	not specified (2)
-	-	1	Congenital myasthenic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.057	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.99
MPC		0.92
ClinPred		0.057	T
GERP RS		5.9
Varity_R		0.86
gMVP		0.78
Mutation Taster		=27/73	disease causing

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

Other links and lift over

dbSNP: rs41265127; hg19: chr2-233396103;