chr2-151680054-ATAAAG-A

Variant names:

• chr2-151680054-ATAAAG-A
• rs553020641
• NM_001164507.2:c.3043-37_3043-33delCTTTA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001164507.2(NEB):​c.3043-37_3043-33delCTTTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,459,110 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (8 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.08
• Publications: 0 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

ACMG classification

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

• BP6: Variant 2-151680054-ATAAAG-A is Benign according to our data. Variant chr2-151680054-ATAAAG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 257808.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00172 (2242/1306746) while in subpopulation MID AF = 0.00548 (30/5472). AF 95% confidence interval is 0.00395. There are 8 homozygotes in GnomAdExome4. There are 1146 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

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.3043-37_3043-33delCTTTA		intron	N/A	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.3043-37_3043-33delCTTTA		intron	N/A	NP_001157980.2
	NEB	NM_001271208.2		c.3043-37_3043-33delCTTTA		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.3043-37_3043-33delCTTTA		intron	N/A	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.3043-37_3043-33delCTTTA		intron	N/A	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.3043-37_3043-33delCTTTA		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152246 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.0263

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00209 AC: 493 AN: 235788 AF XY: 0.00218

Gnomad AFR exome AF: 0.000337

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000946

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00172 AC: 2242 AN: 1306746 Hom.: 8 AF XY: 0.00174 AC XY: 1146 AN XY: 656940

African (AFR) AF: 0.000326 AC: 10 AN: 30660

American (AMR) AF: 0.00178 AC: 76 AN: 42728

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 509 AN: 24966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39022

South Asian (SAS) AF: 0.000757 AC: 62 AN: 81850

European-Finnish (FIN) AF: 0.0000942 AC: 5 AN: 53098

Middle Eastern (MID) AF: 0.00548 AC: 30 AN: 5472

European-Non Finnish (NFE) AF: 0.00144 AC: 1398 AN: 973404

Other (OTH) AF: 0.00274 AC: 152 AN: 55546

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152364 Hom.: 1 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74512

African (AFR) AF: 0.000192 AC: 8 AN: 41576

American (AMR) AF: 0.00170 AC: 26 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0263 AC: 91 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10632

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00194 AC: 132 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00491 Hom.: 1

Bravo AF: 0.00176

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs553020641; hg19: chr2-152536568;