rs114076205

Variant names:

• chr2-151684781-G-A
• rs114076205
• NM_001164507.2:c.2832C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001164508.2(NEB):​c.2832C>T​(p.Ser944Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,587,170 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0070 (4 hom., cov: 32)
  • Exomes 𝑓: 0.011 (92 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.23
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-151684781-G-A is Benign according to our data. Variant chr2-151684781-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00703 (1070/152272) while in subpopulation NFE AF = 0.0111 (754/68026). AF 95% confidence interval is 0.0104. There are 4 homozygotes in GnomAd4. There are 487 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.2832C>T	p.Ser944Ser	synonymous	Exon 28 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.2832C>T	p.Ser944Ser	synonymous	Exon 28 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.2832C>T	p.Ser944Ser	synonymous	Exon 28 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.2832C>T	p.Ser944Ser	synonymous	Exon 28 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.2832C>T	p.Ser944Ser	synonymous	Exon 28 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.2832C>T	p.Ser944Ser	synonymous	Exon 28 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00705 AC: 1072 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00708 AC: 1647 AN: 232524 AF XY: 0.00753

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00510

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00815

GnomAD4 exome AF: 0.0105 AC: 15098 AN: 1434898 Hom.: 92 Cov.: 30 AF XY: 0.0105 AC XY: 7454 AN XY: 710816

African (AFR) AF: 0.00197 AC: 64 AN: 32518

American (AMR) AF: 0.00500 AC: 204 AN: 40764

Ashkenazi Jewish (ASJ) AF: 0.00136 AC: 34 AN: 24996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39394

South Asian (SAS) AF: 0.00642 AC: 523 AN: 81462

European-Finnish (FIN) AF: 0.00535 AC: 283 AN: 52854

Middle Eastern (MID) AF: 0.0136 AC: 77 AN: 5650

European-Non Finnish (NFE) AF: 0.0122 AC: 13391 AN: 1097960

Other (OTH) AF: 0.00880 AC: 522 AN: 59300

GnomAD4 genome AF: 0.00703 AC: 1070 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00654 AC XY: 487 AN XY: 74442

African (AFR) AF: 0.00212 AC: 88 AN: 41556

American (AMR) AF: 0.00771 AC: 118 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4820

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10602

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 754 AN: 68026

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00906 Hom.: 9

Bravo AF: 0.00712

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Nemaline myopathy 2 (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.41
DANN	Benign	0.41
PhyloP100		-1.2
Mutation Taster		=97/3	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: rs114076205; hg19: chr2-152541295;