chr2-232527445-C-T

Variant names:

• chr2-232527445-C-T
• rs115841867
• NM_000751.3:c.243C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001311196.2(CHRND):​c.-29C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,612,212 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (29 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (24 hom.)
• Consequence: CHRND NM_001311196.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.001951
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.635
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-232527445-C-T is Benign according to our data. Variant chr2-232527445-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00844 (1282/151856) while in subpopulation AFR AF = 0.0297 (1232/41418). AF 95% confidence interval is 0.0284. There are 29 homozygotes in GnomAd4. There are 631 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001311196.2. 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.243C>T	p.His81His	splice_region synonymous	Exon 3 of 12	NP_000742.1	Q07001-1
	CHRND	NM_001311196.2		c.-29C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 12	NP_001298125.1
	CHRND	NM_001311195.2		c.-29C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	NP_001298124.1	B4E3W4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRND	ENST00000258385.8	TSL:1 MANE Select	c.243C>T	p.His81His	splice_region synonymous	Exon 3 of 12	ENSP00000258385.3	Q07001-1
	CHRND	ENST00000955151.1		c.243C>T	p.His81His	splice_region synonymous	Exon 3 of 11	ENSP00000625210.1
	CHRND	ENST00000543200.5	TSL:2	c.198+771C>T		intron	N/A	ENSP00000438380.1	Q07001-2

Frequencies

GnomAD3 genomes AF: 0.00840 AC: 1275 AN: 151734 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00210 AC: 527 AN: 251140 AF XY: 0.00139

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000963 AC: 1406 AN: 1460356 Hom.: 24 Cov.: 31 AF XY: 0.000838 AC XY: 609 AN XY: 726610

African (AFR) AF: 0.0315 AC: 1052 AN: 33432

American (AMR) AF: 0.000649 AC: 29 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5706

European-Non Finnish (NFE) AF: 0.000202 AC: 224 AN: 1110810

Other (OTH) AF: 0.00156 AC: 94 AN: 60326

GnomAD4 genome AF: 0.00844 AC: 1282 AN: 151856 Hom.: 29 Cov.: 32 AF XY: 0.00851 AC XY: 631 AN XY: 74164

African (AFR) AF: 0.0297 AC: 1232 AN: 41418

American (AMR) AF: 0.00223 AC: 34 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67962

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00340 Hom.: 27

Bravo AF: 0.00911

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.4
DANN	Benign	0.88
PhyloP100		-0.64
Mutation Taster		=260/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0020
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.12		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: rs115841867; hg19: chr2-233392155; COSMIC: COSV99286133; COSMIC: COSV99286133;