rs10909569

Variant names:

• chr2-151592126-T-C
• rs10909569
• NM_001164507.2:c.14734A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001164508.2(NEB):​c.14734A>G​(p.Asn4912Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0895 in 1,198,524 control chromosomes in the GnomAD database, including 1,068 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict 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 0.12 (73 hom., cov: 30)
  • Exomes 𝑓: 0.087 (995 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.844
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003677845).
• BP6: Variant 2-151592126-T-C is Benign according to our data. Variant chr2-151592126-T-C is described in ClinVar as Benign. ClinVar VariationId is 257743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 73 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.14734A>G	p.Asn4912Asp	missense	Exon 95 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.14734A>G	p.Asn4912Asp	missense	Exon 95 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.14734A>G	p.Asn4912Asp	missense	Exon 95 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.14734A>G	p.Asn4912Asp	missense	Exon 95 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.14734A>G	p.Asn4912Asp	missense	Exon 95 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11602-15772A>G		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.115 AC: 13447 AN: 116724 Hom.: 73 Cov.: 30

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.0365

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.0917

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.0881

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.125 AC: 13666 AN: 109614 AF XY: 0.121

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.0859

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.0868 AC: 93853 AN: 1081670 Hom.: 995 Cov.: 35 AF XY: 0.0882 AC XY: 47045 AN XY: 533108

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

African (AFR) AF: 0.0149 AC: 446 AN: 29852

American (AMR) AF: 0.130 AC: 3262 AN: 25086

Ashkenazi Jewish (ASJ) AF: 0.0973 AC: 1944 AN: 19988

East Asian (EAS) AF: 0.124 AC: 3433 AN: 27768

South Asian (SAS) AF: 0.0669 AC: 4195 AN: 62744

European-Finnish (FIN) AF: 0.171 AC: 5849 AN: 34224

Middle Eastern (MID) AF: 0.0939 AC: 305 AN: 3248

European-Non Finnish (NFE) AF: 0.0842 AC: 70174 AN: 833706

Other (OTH) AF: 0.0942 AC: 4245 AN: 45054

⚠️ 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 AF: 0.115 AC: 13451 AN: 116854 Hom.: 73 Cov.: 30 AF XY: 0.114 AC XY: 6498 AN XY: 57190

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

African (AFR) AF: 0.0232 AC: 884 AN: 38106

American (AMR) AF: 0.130 AC: 1463 AN: 11236

Ashkenazi Jewish (ASJ) AF: 0.0917 AC: 238 AN: 2596

East Asian (EAS) AF: 0.0996 AC: 386 AN: 3876

South Asian (SAS) AF: 0.0884 AC: 336 AN: 3802

European-Finnish (FIN) AF: 0.176 AC: 1330 AN: 7554

Middle Eastern (MID) AF: 0.162 AC: 36 AN: 222

European-Non Finnish (NFE) AF: 0.182 AC: 8552 AN: 47036

Other (OTH) AF: 0.121 AC: 197 AN: 1632

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.195 Hom.: 14

ExAC AF: 0.150 AC: 3745

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.076	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.84
PROVEAN	Benign	0.12	N
REVEL	Benign	0.029
Sift	Benign	0.21	T
Sift4G	Benign	0.44	T
Vest4		0.044
MPC		0.057
ClinPred		0.0028	T
GERP RS		2.6
gMVP		0.0069
Mutation Taster		=99/1	polymorphism (auto)

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: rs10909569; hg19: chr2-152448640; COSMIC: COSV50847635;