rs55921262

Variant names:

• chr2-232526596-G-A
• rs55921262
• NM_000751.3:c.120G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-232526596-G-A
• chr2-232526596-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000751.3(CHRND):​c.120G>A​(p.Lys40Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 1,613,792 control chromosomes in the GnomAD database, including 1,284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (129 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1155 hom.)
• Consequence: CHRND NM_000751.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.75
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-232526596-G-A is Benign according to our data. Variant chr2-232526596-G-A is described in ClinVar as Benign. ClinVar VariationId is 128756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0311 (4735/152296) while in subpopulation NFE AF = 0.0409 (2781/68020). AF 95% confidence interval is 0.0396. There are 129 homozygotes in GnomAd4. There are 2446 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 129 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.120G>A	p.Lys40Lys	synonymous	Exon 2 of 12	NP_000742.1	Q07001-1
	CHRND	NM_001256657.2		c.120G>A	p.Lys40Lys	synonymous	Exon 2 of 11	NP_001243586.1	Q07001-2
	CHRND	NM_001311196.2		c.-152G>A		5_prime_UTR	Exon 2 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.120G>A	p.Lys40Lys	synonymous	Exon 2 of 12	ENSP00000258385.3	Q07001-1
	CHRND	ENST00000543200.5	TSL:2	c.120G>A	p.Lys40Lys	synonymous	Exon 2 of 11	ENSP00000438380.1	Q07001-2
	CHRND	ENST00000955151.1		c.120G>A	p.Lys40Lys	synonymous	Exon 2 of 11	ENSP00000625210.1

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4737 AN: 152178 Hom.: 129 Cov.: 33

Gnomad AFR AF: 0.00620

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0303

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0978

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0409

Gnomad OTH AF: 0.0354

GnomAD2 exomes AF: 0.0314 AC: 7882 AN: 251246 AF XY: 0.0312

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0945

Gnomad NFE exome AF: 0.0400

Gnomad OTH exome AF: 0.0341

GnomAD4 exome AF: 0.0350 AC: 51170 AN: 1461496 Hom.: 1155 Cov.: 34 AF XY: 0.0344 AC XY: 24979 AN XY: 727064

African (AFR) AF: 0.00541 AC: 181 AN: 33480

American (AMR) AF: 0.0203 AC: 906 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 378 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00482 AC: 416 AN: 86258

European-Finnish (FIN) AF: 0.0874 AC: 4637 AN: 53044

Middle Eastern (MID) AF: 0.0180 AC: 104 AN: 5768

European-Non Finnish (NFE) AF: 0.0385 AC: 42821 AN: 1111994

Other (OTH) AF: 0.0285 AC: 1724 AN: 60394

GnomAD4 genome AF: 0.0311 AC: 4735 AN: 152296 Hom.: 129 Cov.: 33 AF XY: 0.0329 AC XY: 2446 AN XY: 74458

African (AFR) AF: 0.00618 AC: 257 AN: 41582

American (AMR) AF: 0.0303 AC: 463 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4826

European-Finnish (FIN) AF: 0.0978 AC: 1038 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0409 AC: 2781 AN: 68020

Other (OTH) AF: 0.0350 AC: 74 AN: 2114

Alfa AF: 0.0290 Hom.: 62

Bravo AF: 0.0246

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0385

EpiControl AF: 0.0411

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		1.7
PromoterAI		-0.0093	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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: rs55921262; hg19: chr2-233391306;