rs181826071

Variant names:

• chr2-151546334-T-C
• rs181826071
• NM_001164507.2:c.20466+11A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BS1 BS2_Supporting

The NM_001164507.2(NEB):​c.20466+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,606,068 control chromosomes in the GnomAD database, including 6 homozygotes. 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 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.763
• Publications: 1 publications found

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124906081 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-151546334-T-C is Benign according to our data. Variant chr2-151546334-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257785.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00196 (298/152280) while in subpopulation NFE AF = 0.00293 (199/68018). AF 95% confidence interval is 0.00259. There are 1 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. 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
	NEB	NM_001164507.2	MANE Plus Clinical	c.20466+11A>G		intron	N/A	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.20466+11A>G		intron	N/A	NP_001157980.2
	NEB	NM_001271208.2		c.20466+11A>G		intron	N/A	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.20466+11A>G		intron	N/A	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.20466+11A>G		intron	N/A	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.15363+11A>G		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 298 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00575

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00179 AC: 439 AN: 245096 AF XY: 0.00189

Gnomad AFR exome AF: 0.000648

Gnomad AMR exome AF: 0.000354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00514

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.00220 AC: 3201 AN: 1453788 Hom.: 5 Cov.: 30 AF XY: 0.00210 AC XY: 1521 AN XY: 723222

African (AFR) AF: 0.000421 AC: 14 AN: 33268

American (AMR) AF: 0.000431 AC: 19 AN: 44100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25906

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85270

European-Finnish (FIN) AF: 0.00529 AC: 282 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5432

European-Non Finnish (NFE) AF: 0.00253 AC: 2801 AN: 1106796

Other (OTH) AF: 0.00141 AC: 85 AN: 60072

GnomAD4 genome AF: 0.00196 AC: 298 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74452

African (AFR) AF: 0.000457 AC: 19 AN: 41574

American (AMR) AF: 0.00105 AC: 16 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00575 AC: 61 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00293 AC: 199 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.00125

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Nemaline myopathy 2 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.081
DANN	Benign	0.41
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs181826071; hg19: chr2-152402848;