2-232531264-GGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT-G

Variant names:

• chr2-232531264-GGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT-G
• rs530117757
• NM_000751.3:c.821-52_821-18delGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000751.3(CHRND):​c.821-52_821-18delGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 948,954 control chromosomes in the GnomAD database, including 10,681 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2161 hom., cov: 28)
  • Exomes 𝑓: 0.17 (8520 hom.)
• Consequence: CHRND NM_000751.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.301
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-232531264-GGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT-G is Benign according to our data. Variant chr2-232531264-GGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	NM_000751.3	MANE Select	c.821-52_821-18delGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT		intron	N/A	NP_000742.1
	CHRND	NM_001256657.2		c.776-52_776-18delGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT		intron	N/A	NP_001243586.1
	CHRND	NM_001311196.2		c.518-52_518-18delGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT		intron	N/A	NP_001298125.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	ENST00000258385.8	TSL:1 MANE Select	c.821-87_821-53delGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT		intron	N/A	ENSP00000258385.3
	CHRND	ENST00000543200.5	TSL:2	c.776-87_776-53delGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT		intron	N/A	ENSP00000438380.1
	CHRND	ENST00000412233.5	TSL:4	n.510-87_510-53delGGACCCTCTAGGACCGGTGCCCCAAGGTCACAGCT		intron	N/A	ENSP00000398143.1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24507 AN: 151292 Hom.: 2162 Cov.: 28

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.0472

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.167 AC: 133061 AN: 797542 Hom.: 8520 AF XY: 0.165 AC XY: 69624 AN XY: 421254

African (AFR) AF: 0.242 AC: 5161 AN: 21288

American (AMR) AF: 0.0866 AC: 3685 AN: 42528

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 4525 AN: 21968

East Asian (EAS) AF: 0.0748 AC: 2695 AN: 36042

South Asian (SAS) AF: 0.168 AC: 12099 AN: 72060

European-Finnish (FIN) AF: 0.174 AC: 8886 AN: 50934

Middle Eastern (MID) AF: 0.231 AC: 881 AN: 3816

European-Non Finnish (NFE) AF: 0.174 AC: 88807 AN: 510564

Other (OTH) AF: 0.165 AC: 6322 AN: 38342

GnomAD4 genome AF: 0.162 AC: 24515 AN: 151412 Hom.: 2161 Cov.: 28 AF XY: 0.162 AC XY: 11996 AN XY: 73964

African (AFR) AF: 0.219 AC: 9034 AN: 41212

American (AMR) AF: 0.121 AC: 1840 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 710 AN: 3472

East Asian (EAS) AF: 0.0473 AC: 243 AN: 5136

South Asian (SAS) AF: 0.158 AC: 754 AN: 4758

European-Finnish (FIN) AF: 0.176 AC: 1849 AN: 10526

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9618 AN: 67802

Other (OTH) AF: 0.160 AC: 334 AN: 2082

Alfa AF: 0.149 Hom.: 199

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs530117757; hg19: chr2-233395974; COSMIC: COSV51327073; COSMIC: COSV51327073;