2-151582622-A-G

Variant names:

• chr2-151582622-A-G
• rs796103760
• NM_001164507.2:c.16021T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_001164508.2(NEB):​c.16021T>C​(p.Leu5341Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.19 (10 hom., cov: 0)
  • Exomes 𝑓: 0.19 (1608 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.629
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 2-151582622-A-G is Benign according to our data. Variant chr2-151582622-A-G is described in ClinVar as Benign. ClinVar VariationId is 257756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.629 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. 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
	NEB	NM_001164507.2	MANE Plus Clinical	c.16021T>C	p.Leu5341Leu	synonymous	Exon 102 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.16021T>C	p.Leu5341Leu	synonymous	Exon 102 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.16021T>C	p.Leu5341Leu	synonymous	Exon 102 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.16021T>C	p.Leu5341Leu	synonymous	Exon 102 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.16021T>C	p.Leu5341Leu	synonymous	Exon 102 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000413693.5	TSL:5	c.211T>C	p.Leu71Leu	synonymous	Exon 2 of 74	ENSP00000410961.1	H0Y786

Frequencies

GnomAD3 genomes AF: 0.189 AC: 166 AN: 880 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.246

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0625

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.273

GnomAD2 exomes AF: 0.0202 AC: 5 AN: 248 AF XY: 0.0149

Gnomad AFR exome AF: 0.0556

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0556

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.0833

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.192 AC: 14892 AN: 77562 Hom.: 1608 Cov.: 0 AF XY: 0.184 AC XY: 7664 AN XY: 41720

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.294 AC: 1263 AN: 4294

American (AMR) AF: 0.223 AC: 923 AN: 4134

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 338 AN: 2468

East Asian (EAS) AF: 0.300 AC: 1102 AN: 3678

South Asian (SAS) AF: 0.144 AC: 2036 AN: 14108

European-Finnish (FIN) AF: 0.215 AC: 596 AN: 2766

Middle Eastern (MID) AF: 0.151 AC: 51 AN: 338

European-Non Finnish (NFE) AF: 0.187 AC: 7797 AN: 41706

Other (OTH) AF: 0.193 AC: 786 AN: 4070

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.190 AC: 169 AN: 890 Hom.: 10 Cov.: 0 AF XY: 0.186 AC XY: 73 AN XY: 392

African (AFR) AF: 0.247 AC: 95 AN: 384

American (AMR) AF: 0.188 AC: 18 AN: 96

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14

East Asian (EAS) AF: 0.286 AC: 12 AN: 42

South Asian (SAS) AF: 0.106 AC: 7 AN: 66

European-Finnish (FIN) AF: 0.0625 AC: 1 AN: 16

Middle Eastern (MID) AF: 0.250 AC: 1 AN: 4

European-Non Finnish (NFE) AF: 0.119 AC: 29 AN: 244

Other (OTH) AF: 0.250 AC: 6 AN: 24

Alfa AF: 0.194 Hom.: 251

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	9.4
DANN	Benign	0.89
PhyloP100		-0.63
Mutation Taster		=99/1	polymorphism

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: rs796103760; hg19: chr2-152439136;